innate immunity

see also:

• immunology
• adaptive immunity
• cytokines

• innate immunity is a term used to refer to all types of immunity excluding adaptive immunity (acquired / adaptive immunity relies upon immune cells such as T-cell and B-cell lymphocytes which produce antibodies and these immune systems arose late in evolution, appearing in vertebrates), and thus is relatively non-specific
• innate immunity is the 1st line of defence against infections and also initiates and controls when the adaptive immune response begins

• intact skin and mucosa
  • the outermost layer of skin, the stratum corneum (SC), consists of corneocytes which are connected by corneodesmosomes, primarily composed of desmoglein-1 (DSG-1), corneodesmosin (CDSN), and desmocollin-1; DSG-1 is expressed on the surface of both corneocytes and keratinocytes;
    • Staph. aureus can cause impetigo by strongly binding to cutaneous desmoglein-1 via serine-aspartate repeat protein D (SdrD) augmented by skin calcium levels (which are often higher in those with atopic dermatitis) and this bond is stronger than any other protein bond known in biology¹⁾
      • S. aureus exfoliative toxins cleave the homophilic interaction site of DSG-1, causing cell detachment and compromising the SC barrier function. Mutations in DSG-1 are linked to dermatitis, multiple allergies, and metabolic wasting;
  • the ATG9A protein in skin cells helps prevent skin inflammation by promoting the autophagy-mediated cleanup of inflammatory proteins within skin cells
    • TNF can trigger an abnormal cGAS/STING-dependent type 1 interferon response, which in turn amplifies skin damage through a molecule called ZBP1. ZBP1 causes excessive death of skin cells when ATG9A is absent, which explains how inflammatory skin diseases such as psoriasis and lupus develop.²⁾
• desquamation helps remove bacteria
• irrigation helps remove organisms
  • eg. tears
• mucus forms a barrier, traps organisms and allows their expulsion
  • in the respiratory tract, mucus expelled via cilia motility mechanisms remove bacteria and fungi
• intestinal barrier made up of the intestinal mucosa, immune cells and the microbiome, shields the body from contents of the gut
  • if this delicate balance of these protective components is disrupted, inflammation, allergies or chronic intestinal diseases can arise
  • the intestinal nervous system acts as a central regulator of the intestinal barrier by using VIP to communicate directly with intestinal LGR5+ stem cells, ensuring that these cells do not multiply too rapidly nor develop excessively into certain cell types. Disruption of this pathway leads to an expansion of tuft cells, enhanced interleukin (IL)-25 production, activation of group 2 innate lymphoid cells (ILC2s) and induction of a type 2 immune response resembling worm expulsion. This phenotype occurs independently of the microbiota but is modulated by the IL-25R–ILC2–IL-13 axis and dietary solid food intake. ³⁾
• commensal organisms form a normal flora which helps prevent colonisation by more pathogenic flora

• an important part of innate immunity is mucus production which forms a barrier to invading organisms
• mucus consists of mucins which are glycan sugars and recently, it has been discovered a symbiotic relationship exists whereby certain strains of bacteriophage viruses bind to the mucins and reduce binding of bacteria to the mucin by over 10,000 fold, thereby further reducing bacterial invasion.
  • an example is crAssphage which was discovered in 2014 and appears to specifically target Bacteroides sp of bacteria in the gut

• cutaneous microbiomes:
  • conditions like atopic dermatitis, psoriasis, and acne are tightly linked to microbial imbalance
    • in atopic dermatitis, reduced filaggrin (a protein crucial for barrier function) leads to overgrowth of S. aureus, which worsens inflammation by stimulating T-helper 2 (Th2) cells through cytokines like Interleukin-33 (IL-33) and Thymic Stromal Lymphopoietin (TSLP).
    • psoriasis is driven by the Interleukin-23–Interleukin-17 (IL-23–IL-17) axis. Staph. warneri and Candida albicans worsen lesions, while Staph. cohnii appears protective, likely by suppressing IL-17 signaling
    • acne severity correlates with reduced microbial diversity and increased abundance of Firmicutes and Enterococcus species
  • commensals like Staph. epidermidis support wound healing
  • commensal microbes engage in constant crosstalk with skin-resident immune cells like macrophages, Dendritic Cells (DCs), gamma-delta (γδ) T cells, and Innate Lymphoid Cells (ILCs).
    • commensal microbiota colonization of skin wounds shape CXCL10–bacterial DNA complexes, which activate plasmacytoid dendritic cells (pDCs) to produce type I interferons. These pDCs promote tissue repair through macrophage-mediated processes.
    • commensal skin microbiota stimulate keratinocytes to produce stem cell factors (SCFs), which induce mast cell maturation
    • S. epidermidis produces ceramides and inducing commensal-specific T cells through interactions with DCs and Treg cells via peptide ligand and antigen recognition and thus strengthens the skin barrier, promotes tissue repair, maintains homeostasis and induces tolerance to commensal microorganisms.
    • S. epidermidis can exacerbate skin inflammation through the expansion of γδ T cells
    • S. epidermidis may shift from symbiont to threat by producing lipases and proteases
  • S. hominis inhibits the growth of pathogens, such as Staphylococcus aureus
  • C. acnes, produce propionic acid (a short-chain fatty acid) that strengthens the skin barrier by activating Peroxisome Proliferator-Activated Receptor-Alpha (PPARα) in keratinocytes but also contributes to inflammation via γδ T cell expansion
  • microbial metabolites, such as indole-3-aldehyde and quinolinic acid, activate the Aryl Hydrocarbon Receptor (AhR) pathway in keratinocytes. This pathway inhibits TSLP and the NLRP3 inflammasome, thereby attenuating atopic dermatitis and psoriasis.
  • Malassezia has been shown to inhibit S. aureus biofilm formation
    • S. aureus α-toxin, activates Protease-Activated Receptor 1 (PAR1) in neurons, causing itching and damage, and limits Treg formation, leading to immune activation instead of tolerance.
  • early life microbiomes:
    • first encounters with skin microbiota during infancy leave lasting marks ⁴⁾
      • exposure to riboflavin-producing bacteria, such as S. epidermidis, promotes the long lasting development of Mucosal-Associated Invariant T (MAIT) cells and Regulatory T (Treg) cells, which are essential for immune tolerance.
      • mice studies have shown that early exposure to S. aureus may even protect against the development of atopic dermatitis later in life
      • early antibiotic exposure or disruption of the skin barrier during infancy can lead to increased inflammation and diseases such as psoriasis in adulthood

• lysozyme (LYZ)
• defensins are small cysteine-rich cationic proteins
  • defensins and lysozyme amongst many other roles are the main first line defenses of the conjunctiva and both play central roles in neonate immunity via human breast milk
  • alpha defensin peptides are increased in chronic inflammatory conditions and in some cancers and imbalance of defensins may have a role in acne
  • defensins also play a role in skin healing and are also found in psoriatic skin
• cathelicidins
  • a family of antimicrobial peptides characterized by a conserved cathelin domain and a variable antimicrobial peptide domain
  • disrupt bacterial cell membranes, leading to cell death.
  • can modulate the activity of various immune cells and influence inflammatory processes and can also promote wound healing and angiogenesis
  • human cathelicidin LL-37 is expressed in various cells and tissues, including neutrophils, epithelial cells, and macrophages
• some peptides derived from glycosaminoglycan-binding proteins (HBPs) have antimicrobial activity
  • these proteins normally aid in blood clotting and inflammation
  • some peptides derived from these have high potency and specificity for bacteria, with a very low toxicity in human cells
    • HBP-5, has shown particular promise as a therapeutic antimicrobial against multi-resistant Gram negative bacteria such as Escherichia coli, Pseudomonas aeruginosa and Acinetobacter baumannii: ⁵⁾
      • not only does it effectively kill bacteria in the laboratory even at very low concentrations, but it also acts as a model of sepsis
• albumin
  • appears to be able to nullify critical virulence factors including toxins and other fungal proteins such as in mucormycosis - albumin-bound free fatty acids (FFAs) suppress the expression of key virulence factors of the fungus Mucorales by inhibiting protein synthesis - albumin prevents FFA oxidation, which otherwise abolishes their antifungal properties ⁶⁾

• pattern recognition receptors (PRRs)
  • bind pathogen-associated molecular patterns (PAMPs) and induce inflammatory responses and cell death
  • particularly for intracellular pathogens such as viruses
  • Toll-like receptors
    • the main pattern recognition receptors for identifying foreign RNA are the Toll-like receptors TLR7 and TLR8, which are located in specific cell organelles called endolysosomes
    • the RNAs must first be broken down by certain enzymes in the endolysosomes before they can be recognized by the receptors
    • this can be evaded in mRNA vaccinations by using modified RNA containing pseudouridine instead of uridine is less easily processed by lysosomal enzymes while the receptors also fail to recognize the pseudouridine-containing fragments. This avoids unwanted excessive inflammation.
      • pseudouridine is also a modification of cellular RNAs that is widespread in nature, particularly in vertebrate RNA.
  • cytoplasmic nucleotide-binding-oligomerization-domain- (NOD-) like receptors
  • retinoic acid-inducible gene I (RIG-I)-like receptors

• respiratory epithelial cells infected by influenza and other viruses trigger an internal pathway which results in gasdermin D and gasdermin E proteins being processed such that pores form in the cell membrane which release cytokines which in turn trigger immune response and that cell's death with resultant reduced viral loads.⁷⁾

• see inflammation
• urokinase plasminogen activator receptor (UPAR)
  • uPAR is a multiligand, membrane-bound receptor expressed on immune and endothelial cells, where it regulates immune activation, cell adhesion, and tissue remodeling
    • membrane-bound uPAR is best known for its key role in regulating the plasminogen activation system by binding uPA, a serine protease, when bound to uPAR, it catalyzes the conversion of inactive plasminogen into active plasmin, leading to the degradation of ECM proteins like fibrin.
    • uPAR binds vitronectin, a major ECM component, promoting the initial attachment of cells to the matrix, as well as to various integrins
      • uPAR-α3β1 integrin interactions are crucial for tumor cell migration, invasion, and metastasis via activation of the MAPK/ERK pathway
      • while uPAR and its associated proteins do not directly bind Toll-like receptors (TLRs), they can influence TLR signaling by interacting with integrins. These indirect interactions help amplify immune responses by modulating the production of inflammatory cytokines like TNF-α, IL-6, and IL-1β.
    • in immune cells, uPAR is involved in immune signaling, cell migration, and chemotaxis;
    • in endothelial cells, it responds to injury or inflammation;
    • in fibroblasts, it aids in tissue repair and extracellular matrix (ECM) remodeling;
    • in epithelial cells, it supports tissue remodeling and repair;
    • in adipocytes, it contributes to metabolic dysfunction and ECM remodeling, affecting fat tissue plasticity and structure
  • uPAR undergoes glycosylphosphatidylinositol (GPI)-anchor cleavage and proteolytic processing to generate circulating proteins, including suPAR and the fragments D1 and D2D3
  • all uPAR-derived circulating proteins participate in immune signaling and integrin-mediated cell activation
  • the uPAR fragment D2D3 has been implicated in both kidney injury and pancreatic β-cell dysfunction
  • suPAR may influence renal tubular cell metabolism - in vitro studies have shown that suPAR increases ATP production, mitochondrial superoxide generation, and energetic demand in proximal tubular epithelial cells, potentially sensitizing them to injury and helping explain clinical associations with acute kidney injury (AKI)
  • a missense variant (rs4760) in the PLAUR gene (this gene encodes a pre-uPAR protein) is associated with increased circulating suPAR levels
    • minor allele frequency (MAF) of rs4760 is 16% in European-ancestry populations but 0% in African-ancestry populations ⁸⁾
  • bone marrow–derived immature myeloid cells, neutrophils, monocytes-macrophages and dendritic cells are considered the primary sources of suPAR during acute immune activation, making circulating suPAR a marker of systemic innate immune activity
  • under stable, non-acute conditions, an individual’s suPAR levels remain remarkably consistent, typically fluctuating by less than 10% over five years
  • cigarette smoking is a potent stimulator of circulating suPAR levels
  • some acute infections increase suPAR levels, particularly, RNA viral infections, including HIV and SARS-CoV-2, as well as some bacterial infections.
  • suPar as biomarker of overactive or dysregulated innate immune system and possible key driver of chronic kidney, metabolic and cardiovascular diseases ⁹⁾
    • unlike acute-phase reactants such as interleukin-6 or C-reactive protein, suPAR levels remain stable during acute illness and show minimal circadian variation
    • raised suPar levels have been associated with subclinical atherosclerosis, and future cardiovascular events as well as chronic kidney disease progression¹⁰⁾
    • suPAR outperforms traditional inflammatory markers, like hsCRP and IL-6, in predicting atherosclerosis, myocardial infarction, and heart failure
• major histocompatibility complex (MHC) class III and IV:
  • unlike MHC class I and II systems (which have genes on either side of the 61 MHC class III and IV genes on chromosome 6 and which activate the T lymphocytes), MHC class III and IV genes are mainly involved in the innate system by coding signalling proteins such as TNF, heat shock protein and complement, and are mainly produced by the liver and by macrophages
• cell damage-associated molecular pattern (DAMP):
  • high mobility group box 1 (HMGB1)
    • an intracellular protein which has a significant role in stabilizing chromosome structure and controlling gene expression
    • during cell stress, HMGB1 can be translocated and modified to the cytosol. It is then secreted into the extracellular space—where it acts as an alarm that triggers DAMP immune response, and thus serum levels can act as a biomarker of immune activation
• Stimulator of Interferon Genes (STING) protein mediated innate immune response
  • STING responses are crucial for clearing pathogens and in particular, cells with cytosolic DNA (which is usually from pathogens but can be from build up of nuclear DNA-protein crosslinks not removed by the enzyme SPRTN)¹¹⁾
  • unrestrained STING activity can cause a variety of auto-immune pathologies
  • STING is “turned off” via endosomal sorting complex required for transport (ESCRT) that packages STING into small compartments to allow it to be degraded, or broken down, by the lysosome ¹²⁾
  • the STING pathway is also very important in eliminating tumour cells
    • in 2023, a vaccine designed to be injected into tumours has been developed to restore STING signaling and eliminating the majority of tumors in mouse models of colon cancer and melanoma, with minimal side effects. The vaccine also inhibited metastasis in a breast cancer mouse model and prevented the recurrence of tumors in cured mice. CD8+ T cells, and, seemingly paradoxically, CD4+ T cells play pivotal roles in achieving this anti-tumour immunity. STING signaling polarized the CD4+ T cells into the T helper Type I (TH1) phenotype, a helper T cell that activates other immune cells to attack tumor cells. Such a vaccine administered systemically could have severe unwanted effects. ¹³⁾
  • the STING pathway is also impacts the immune system in other ways, including the maturation, specialization, and activation of certain types of immune cells.
• pathogen-recognition receptors (PRRs)
  • the signature of exogenous pathogens, known as pathogen-associated molecular patterns, is recognized in the infected lesion by pathogen-recognition receptors (PRRs) of immune cells such as monocytes and macrophages
  • These PRRs comprise Toll-like receptors (TLRs), retinoic acid-inducible gene-1-like receptors, nucleotide-binding oligomerization domain-like receptors, and DNA receptors.
  • They stimulate a range of signaling pathways including NF-κB, and enhance the transcription of the mRNA of inflammatory cytokines such as IL-6, tumor necrosis factor (TNF)-α, and IL-1β.
  • TNF-α and IL-1β then activate transcription factors to produce IL-6.¹⁴⁾
• damage-associated molecular patterns (DAMPs), are released from damaged or dying cells in noninfectious inflammations such as burn or trauma, directly or indirectly promote inflammation.
• cells involved include:
  • mast cells
  • neutrophils
  • eosinophils
  • basophils
  • macrophages and dendritic cells
    • in Dec 2023, it was discovered that a specific polyprenylated polycyclic acylphloroglucinols (PPAP), PPAP53, a non-natural derivative, is able to activate human macrophages to fight drug resistant tuberculosis bacteria without being toxic to the macrophages themselves ¹⁵⁾
      • hyperforin, a natural type A PPAP from St. John’s wort, exhibits antidepressant and antibacterial effects also against Mtb but is too unstable which limits the utility in clinical practice
    • a 2025 study showed that electrical stimulation via a bioreactor can reprogram macrophages - stimulation caused a shift of macrophages into an anti-inflammatory state that supports faster tissue repair; a decrease in inflammatory marker (signalling) activity; an increase in expression of genes that promote the formation of new blood vessels (associated with tissue repair as new tissues form); and an increase in stem cell recruitment into wounds (also associated with tissue repair)¹⁶⁾
    • a DNA polymerase protein called Polμ, in addition to being important in lymphocyte development, is essential to the wound repair process, as it enables macrophages to avoid apoptosis induced by ROS at the site of inflammation in an environment of reactive oxygen species (ROS) which they have produced.¹⁷⁾
  • natural killer cells - mainly target intracellular infections
    • gut metabolite butyric acid restores the function of CX3CR1-positive natural killer cells, a population critical for early immune defense in the lungs - butyric acid activates the PI3K/AKT signaling pathway, increasing CX3CR1 expression and strengthening NK cell cytotoxicity and migratory capacity.¹⁸⁾
  • platelets
    • during severe pathological conditions such as infections or infarction, platelets can switch from pro-thrombotic functions to pro-inflammatory by creating and shedding tiny, filamentous membrane extensions called Platelet-derived Integrin and Tetraspanin rich Tethers (PITTs) that are rich in αIIbβ3 and the tetraspanin co-receptor CD9 which bind to neutrophils and endothelial cells, anchoring them to each other and activate inflammatory response of neutrophils and thereby amplify vascular inflammation - the detaching platelets partially depleted of αIIbβ3 lose their normal clotting function ¹⁹⁾
  • etc
• biochemical mechanisms include:
  • histamine release
  • reactive oxygen species (ROS)
  • cytokines
  • chemokines
  • pentaxins (CRP, pentraxin 3 (PTX3))
  • JAK-STAT signalling
  • NOD/RIPK2 signalling pathway
    • NOD/RIPK2 signalling pathway is a key arm of the innate immunity system, playing critical roles both in clearing bacterial infections and maintaining immune homeostasis
    • intracellular nucleotide-binding oligomerisation domain (NOD) receptors are activated by bacterial cell wall breakdown products and additional damage-associated molecular patterns
    • activated NOD receptors signal through the RIPK2, stimulating the MAPK and NF-κB pathways to elicit tissue-specific responses, most notably inflammatory responses
    • NOD/RIPK2 signalling is tightly regulated, as mutations that either abrogate or elevate signalling are associated with chronic inflammatory diseases, including osteoarthritis, Crohn's, Blau syndrome, early-onset sarcoidosis and Behcet's disease. Variants affecting the NOD/RIPK2 signalling pathway are associated with divergent forms of familial OA, while an OA-associated RIPK2 gene variant encoding a single amino acid change in the kinase domain is sufficient to alter basal gene expression patterns in primary chondrocytes and bone marrow macrophages and confer increased susceptibility to post-traumatic OA²⁰⁾
• identification of bacteria as pathogens by the innate system usually relies upon the presence of lipopolysaccharide coatings on the bacteria which contain 6 acyl chains that are not too long
  • the protein GBP1 can coat pathogens and directly break their cell walls by tightening around it ²¹⁾
  • NB. most interleukins are mainly produced by T cells hence are part of the acquired immune system although interleukin-6 (IL-6) is produced by a variety of cells
• phagocytosis of cells is important for intracellular virus or bacterial infections, and xtracellular bacteria and protozoa, but not useful for fungi or intracellular protozoa
• coagulation may play a role
• some bacteria once inside a macrophage can release toxins to stop the functioning of mitochondria and this then triggers the cell to undergo apoptosis ²²⁾

• mainly activated in response to invading extracellular organisms
• see complement

• it appears platelets are important in normal function of monocytes in the immune reaction
• immune thrombocytopenia (ITP) or the artificial removal of platelets from healthy monocytes results in “immunoparalysis” while supplementing monocytes with fresh platelets reverses this condition and restores the monocyte cytokine response ²³⁾
• pro-inflammatory signals, including NF-κB and p38 MAPK, propagate from platelets to monocytes and maintain their inflammatory capacity
  • platelets overcome NF-κB2 and p38 MAPK ablation in human monocytes
• platelets are essential for PRR-induced cytokine responses of human monocytes

• the hypothalamus regulates innate immune responses through the hypothalamic-pituitary-adrenal cortex (HPA) axis, a key component of the neuro-immune interface
• activation of the neuro-immune axis led to directed activation of the innate lymphoid cells and reduced frequency of these cells - this suggests their migration into the tissues
• it appears this can be activated by a perceived virtual infectious threat ²⁴⁾

• it seems that in mice, dietary methionine increases the kidneys' filtration capacity, improving blood flow and helping the body excrete pro-inflammatory cytokines through the urine and thereby reducing the damaging inflammatory response, apparently without hindering other key aspects of the immune response and improving ability to respond to Yersinia pseudotuberculosis infection.²⁵⁾

• regulation of the inflammatory response is important to ensure undue damage does not occur from the inflammatory response
• a complex feedback network of regulatory signals determines the appropriate degree of inflammation based on initial and ongoing cues
• some of the mechanisms involve the above systems including the removal of pro-inflammatory triggers such as dead cells, pathogens, etc
• macrophage phenotypic switching from pro-inflammatory (M1) to reparative (M2)
• clearance of apoptotic cells (efferocytosis)
• production of anti-inflammatory cytokines (IL-10, TGF-beta)
  • mainly via macrophages
• decoy receptors and inhibitors
  • inhibitory proteins to deactivate inflammatory cascades
  • IL-1 receptor type II (CD121b) acts as a decoy receptor to neutralize excessive IL-1b
  • specific proteins inhibit complement activation
• adenosine generation
  • ecto-enzymes CD39 and CD73 can convert extracellular ATP into adenosine, which acts as a potent signaling molecule to suppress inflammation and promote Treg cell differentiation
• resolution of complement and coagulation
  • activated components of the complement system are rapidly deactivated to prevent excessive tissue damage
• action of regulatory cells
• reversible oxidation/reduction reactions involving the thiol groups of cysteine (Cys) residues, maintaining redox homeostasis and protecting cells from oxidative damage
  • glutathione (GSH)
    • formed from cysteine
  • thioredoxin
    • an oxidative stress-limiting protein with anti-inflammatory and antiapoptotic properties
    • can also promote differentiation of macrophages into an alternative, anti-inflammatory M2 phenotype ²⁶⁾
    • may have neuroprotective roles following mild traumatic brain injury and may help to reduce progression to recurrent seizures and neurodegeneration²⁷⁾²⁸⁾

• anti-viral innate immunity includes²⁹⁾:
  • pattern recognition receptors (PRRs) which bind pathogen-associated molecular patterns (PAMPs) and induce inflammatory responses and cell death
    • membrane-bound Toll-like receptors (TLRs)
    • cytoplasmic nucleotide-binding-oligomerization-domain- (NOD-) like receptors
    • retinoic acid-inducible gene I (RIG-I)-like receptors
  • coagulation factors
  • complement components
  • interferons
    • in respiratory viral infections these are mainly produced by plasmacytoid D.C.s (secrete most of the IFN-1), and also by epithelial cells, endothelial cells, alveolar macrophages, N.K.s, and inflammatory monocyte macrophages
  • cytokines such as IL-1β and IL-6
    • IL-23 acts on group 3 innate lymphoid cells (ILC3s), a family of immune cells that are a first line of defense in mucosal tissues such as the intestines and lungs. In response, ILC3s increase activity of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), a key regulatory factor that prevents the immune system from attacking the body and beneficial gut microbiota. This interaction critically balances the pro-inflammatory effects of IL-23 to maintain gut health, but is impaired in IBD. ³⁰⁾
  • chemokines
    • see also https://en.wikipedia.org/wiki/Chemokine
    • chemokines or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells
    • homeostatic chemokines are constitutively produced in the thymus and lymphoid tissues and are responsible for basal leukocyte migration
      • eg. CCL14, CCL19, CCL20, CCL21, CCL25, CCL27, CXCL12 and CXCL13.
    • inflammatory chemokines are formed under pathological conditions (on pro-inflammatory stimuli, such as IL-1, TNF-alpha, LPS, or viruses) and actively participate in the inflammatory response attracting immune cells to the site of inflammation.
      • CXCL-8 (IL-8, chemoattractant for neutrophils), CCL2, CCL3, CCL4, CCL5, CCL11 (chemoattractant for eosinophils via CCR3 receptor), CXCL10
      • CXCL17, a protein predominantly found in mucosal tissues such as the lungs and which plays a crucial role in combating infections by recruiting immune cells to affected sites, has been identified as a potent inhibitor of the CXCR4 chemokine receptor via use of glycosaminoglycans. CXCL17 is a chemokine principally expressed by mucosal tissues, where it facilitates chemotaxis of monocytes, dendritic cells, and macrophages and has antimicrobial properties and has been implicated in the pathology of inflammatory disorders and progression of several cancers, and its expression is increased during viral infections of the lung. ³¹⁾
  • heat shock proteins (HSPs)
    • essential for innate immunity
    • “in early infection, HSPs are upregulated, acting as DAMPs, which are released into the extracellular space to signal significant peripheral cell damage to the cells of the innate immune system, especially antigen-presenting cells (APCs)”
    • “HSPs interact with CD14, CD91, TLR2, and TLR4 receptors to mediate macrophages and dendritic cells to produce cytokines such as TNF-α, IFN-α, IL-1β, IL-6, IL-12, and GM-CSF”
    • “HSPs can stimulate dendritic cell maturation and migration, open the Toll/IL-1 signaling pathway, and induce rapid calcium flux, I-κBα phosphorylation, and NF-κB activation ”
  • inflammatory body sensors to directly and indirectly detect viruses or viral components:
    • cyclic GMP-AMP synthase (cGAS)
    • stimulator of interferon genes (STING)
  • cellular components typically prevent the spread of viral infection:
    • activated macrophages act as the first line of defense against pathogens and heterologous materials when they invade the lung and limit viral replication and spread partly by producing macrophage extracellular traps (METs)
    • induced maturation of dendritic cells via via the nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways resulting in increasing the expression of cell surface molecules such as CD80, CD86, and MHC-II as well as inflammatory cytokine production like tumor necrosis factor-a (TNFα), IL-1β, IL-6, and IL-12p70
    • neutrophils form neutrophil extracellular traps (NETs) and form the NETs-IL-1 loop which activates the NLRP3 inflammasome in lung macrophages and in turn, this activates the NET-IL-1 loop
    • Natural killer (N.K.) cells (adaptive N.K. cells and armed CD56 N.K. cells) are crucial in controlling viral infection as they can target the virus and have anti-fibrotic activity
    • other innate lymphoid progenitor cells, and γδT cells
• innate immunity against respiratory viruses tends to wane as we get older, more obese, more psychologically stressed
  • “anxiety and depression regulate complement signaling pathways through neurotransmitter action… changes in complement are closely related to the transfer of lymphocytes and the strength of innate immunity”, and “chronic stress can induce immune damage through harmful modulation of gut-brain axis activity, thus affecting the innate immune system's ability to fight” ³²⁾

• the caudal nucleus of the solitary tract (cNST)
  • this part of the brainstem plays a key role in body-brain axis and has important connections with the vagus nerve
  • in a 2024 mice study where mice are given a bacterial compound that sets off innate immune responses³³⁾:
    • chemically suppressing the cNST resulted in an out-of-control inflammatory response to the immune insult: levels of pro-inflammatory molecules released by the immune system were more than three times higher than usual, and levels of anti-inflammatory immune compounds were roughly three times lower than normal.
    • artificially activating the cNST reduced pro-inflammatory molecule levels by nearly 70 percent and increased anti-inflammatory chemical levels almost tenfold
    • this suggests there is a significant mind-body inflammation role