THE ACTIVATION OF TLR OR IL-1R IN MICROGLIA MEDIATES NEUROINFLAMMATION THROUGH IRAK

A. Avivar-Valderas^1* and M.J. Conti²

¹ Takeda, Cell therapy sciences, Tres Cantos, Madrid, Spain;
² Faculty of Medicine, S. Andrea University “La Sapienza”, 00189 Rome, Italy.

*Correspondence to:
Dr. Alvaro Avivar-Valderas,
Takeda, Cell therapy sciences
Marconi 1, 28760, Tres Cantos,
Madrid, Spain.
e-mail: Alvaro.avivar@takeda.com

Received: 03 July, 2025 Accepted: 31 October, 2025

ISSN 2279-5855 print ISSN 2974-6345 online. Copyright © by BIOLIFE 2025 This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: All authors report no conflicts of interest relevant to this article.

ABSTRACT

Interleukin-1 receptor-associated kinase (IRAK) belongs to a family of intracellular kinases that mediate the innate immune response after antigen binds to Toll-like receptors (TLRs) and the interleukin-1 receptor (IL-1R). IRAKs 1, 2, 3, and 4 recognize pathogen-associated molecular patterns (PAMPs). In neuroinflammation, IRAK1 and IRAK4 mediate microglial activation, which has been noted in neurological disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). IRAK is involved in both immune and inflammatory processes when inflammatory cytokines are dysregulated, and the activating antigens can be diverse. IRAK4 and IRAK1 promote inflammation, while IRAK3 has a regulatory/inhibitory role and limits the excessive inflammatory response in microglia. IRAK inhibitors, especially IRAK4, are being studied as potential therapeutic agents to reduce neuroinflammation.

KEYWORDS: Interleukin-1 receptor-associated kinase, intracellular kinase, Toll-like receptor, neuroimmunology, neuroinflammation, neurodegenerative disorder

INTRODUCTION

Interleukin-1 Receptor–Associated Kinase (IRAK) is a family of intracellular kinases that play an important role in immune signaling after activation of Toll-like receptors (TLRs) and the interleukin-1 receptor (IL-1R) (1). IRAK is crucial for the activation of innate immune cells and the inflammatory response (2).  IRAK comprises four proteins: IRAK1, 2, 3, and 4 (3).  In the cellular activation cascade and following the response of TLRs and IL-1R, which recognize pathogen-associated molecular patterns (PAMPs), IRAK exerts biological transcriptional activity after recruiting the crucial adaptor myeloid differentiation primary response 88 (MyD88) (4). MyD88 recruits IRAK4, which in turn phosphorylates and activates IRAK1 and/or IRAK2 (5). IRAK4 and IRAK1 play an important role in the antibacterial response, but also in antiviral responses, albeit indirectly (6). The immune response to viruses is largely mediated by TLR3, which recognizes double-stranded RNA, TLR7/8, which recognize single-stranded RNA, and TLR9, which recognizes viral DNA (7).

DISCUSSION

The IRAK family of kinases plays an important role in the field of neuroimmunology and neuroinflammation (8).  In innate immunity, the IRAK family consists of four main members: IRAK1, IRAK2, IRAK3 (IRAK-M), and IRAK4, involved in immune receptor signaling (9).  In the central nervous system (CNS), IRAK is not directly linked to the pathophysiology of neurons but plays a key role in the inflammatory response mediated by microglia and the inflammatory modulation exerted by astrocytes (10). Activation of the IL-1 receptor (IL-1R) or TLR activates the inflammatory pathway initiated by MyD88, leading to the activation of IRAK and NF-κB/MAPK, with the production of inflammatory cytokines such as IL-1β, TNF, and IL-6 (11, 12). Thus, IRAK activation in the CNS leads to neuroinflammation, as occurs in Alzheimer’s Disease (AD) and Parkinson’s Disease (PD), multiple sclerosis (MS), stroke, and ischemic injury (13).

IRAK1 and IRAK4 mediate microglial activation in the neuroinflammation seen in AD; while in PD, IRAK3 is involved and plays a role in the loss of negative regulation of inflammation (14). Furthermore, IRAK1 and IRAK4 are important in acute myeloid leukemia, where they participate in the survival of leukemic cells (15). The inflammatory response may manifest with low-grade fever, but it may also be absent and show no increase in white blood cell count or inflammatory markers (16). This immunodeficiency can lead to increased vulnerability to bacterial infections, while IRAK1 overactivity can cause autoimmune disease (17).

Currently, drugs that inhibit IRAK4 are being studied for the inhibition of inflammation and cancer. IRAK4 deficiency leads to recurrent infections with pyogenic bacteria, particularly Streptococcus pneumoniae and Staphylococcus aureus, but other types of bacteria may also be involved (18). Viruses activate the immune system via TLR7 and TLR9 leading to stimulation of myeloid differentiation primary response 88 (MyD88) and NF-κB with activation of innate immune cells, natural killer (NK) cells, and macrophages (19).

IRAK1 and IRAK4 play an important role in many inflammatory diseases, including autoimmune diseases and cancer (20).  Autoimmune diseases involving IRAK1 are diverse and include systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjogren’s syndrome, and those involving IRAK4 include Crohn’s disease, MS, and RA (21,22). IRAK3 is also involved in allergic diseases and bronchial asthma (23). IRAK1 and IRAK4 are implicated in B-cell lymphoma, where a MyD88 mutation activates NF-κB (24). IRAK1 is important in ovarian and breast cancer, where it promotes invasiveness and drug resistance, and IRAK4 is associated with tumor inflammation and disease progression of pancreatic cancer (25,26).

Mutations in IRAK can cause immunodeficiency, especially those affecting the innate immune response. IRAK4 mutations are known to lead to primary immunodeficiency, an autosomal recessive genetic deficiency that causes a defect in the TLR/IL-1R pathway, inhibiting the production of IL-1β and TNF (27). IRAK4 genetic mutations cause a primary immunodeficiency disorder characterized by recurrent bacterial infections, a reduced inflammatory response, and dysfunction of the innate immune response, effects that are less severe in the IRAK1 mutation (28). IRAK4 inhibitors are in the preclinical phase for diseases such as SLE, RA, lymphomas, and leukemia (29).

IRAK, and in particular, IRAK4 and IRAK1, are important in the immune response to microorganisms recognized by TLRs and IL-1R. After TLR and/or IL-1R activation, IRAK4 and IRAK1 are recruited via MyD88, initiating the inflammatory cascade. Activation of the MyD88 pathway, IRAK, and TRAF6 occurs through IRAK4, which activates IRAK1/2 and phosphorylation. IRAK1 binds to TRAF6 and activates TAK1, which in turn activates IKK and MAPK, reactions that lead to the production of cytokines such as IL-1, TNF, IL-6, and interferon (IFN), and the elimination of viruses, bacteria, or fungi.

CONCLUSIONS

In conclusion, IRAK, an intracellular kinase, mediates the innate immune response by binding to TLRs and IL-1R in CNS microglia. Activation begins with the involvement of MyD88, leading to the activation of IRAK and NF-κB/MAPK with the production of inflammatory cytokines, while IRAK3 has a regulatory/inhibitory role. Activation of NF-κB/MAPK by IRAK leads to neuroinflammation, which occurs in neurological diseases such as AD, PD, MS, and Crohn’s disease. Inhibition of inflammatory IRAK offers new therapeutic hope for neuroinflammatory diseases.

Conflict of interest

The authors declare that they have no conflict of interest.

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