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
• 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 ³⁾
      • 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: ⁴⁾
      • not only does it effectively kill bacteria in the laboratory even at very low concentrations, but it also acts as a model of sepsis

• 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.⁵⁾

• see inflammation
• 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
  • 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 ⁶⁾
  • 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. ⁷⁾
  • the STING pathway is also impacts the immune system in other ways, including the maturation, specialization, and activation of certain types of immune cells.
• 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 ⁸⁾
      • 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)⁹⁾
  • natural killer cells - mainly target intracellular infections
  • etc
• mechanisms utilise histamine, cytokines, chemokines, pentaxins (CRP, pentraxin 3 (PTX3)), JAK-STAT signalling etc
  • 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 ¹⁰⁾
• 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 ¹¹⁾

• 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 ¹²⁾
• 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 ¹³⁾

• anti-viral innate immunity includes¹⁴⁾:
  • 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. ¹⁵⁾
  • 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. ¹⁶⁾
  • 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” ¹⁷⁾

• 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 responses¹⁸⁾:
    • 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