1. Introduction

The immune system is a finely tuned network of cells and molecules that stands as the body's first line of defense against invading pathogens and endogenous threats. Among the guardians of this intricate defense mechanism, NOD-Like Receptors (NLRs) emerge as versatile sentinels, primarily positioned within the cellular interior to detect and respond to various danger signals. These receptors are part of the pattern recognition receptor (PRR) family, functioning as crucial components of the innate immune system.

This research embarks on an exploration of the multifaceted world of NLRs, beginning with their structural attributes, classification into subfamilies, and the intricate signaling pathways they engage. We will uncover the diverse roles played by NLRs in innate immune activation, inflammation, and the regulation of immune responses. Furthermore, the researchers will delve into the involvement of NLRs in various disease contexts, including infectious diseases, autoinflammatory disorders, and cancer. Additionally, the researchers will explore the exciting potential of targeting NLRs for therapeutic intervention to modulate immune responses and combat a range of debilitating conditions. (Its a summary from the book Kuby Immunology ^[1])

2. Structural Diversity and Classification of NLRs

NLRs are characterized by their central nucleotide-binding and oligomerization (NACHT) domain, a C-terminal leucine-rich repeat (LRR) domain for ligand recognition, and an N-terminal effector domain that determines their functional specificity. Based on the N-terminal effector domain, NLRs are classified into three main subfamilies:

1. NLRA (NLR with an acidic transactivation domain): This subfamily includes NLRA1 (CIITA), which plays a role in regulating major histocompatibility complex (MHC) class II gene expression.

2. NLRB (NLR with a baculoviral inhibitory repeat): The NLRB subfamily consists of NAIPs (NLR family apoptosis inhibitory proteins), which are involved in the recognition of bacterial proteins, particularly those of the type III secretion system.

3. NLRC (NLR with a caspase recruitment domain): NLRC subfamily members, such as NOD1 (NLRC1) and NOD2 (NLRC2), are known for their roles in detecting peptidoglycans from bacterial cell walls.

4. NLRP (NLR with a pyrin domain): The NLRP subfamily, including NLRP1, NLRP3, and NLRP6, forms inflammasomes that activate caspase-1 and promote the maturation of proinflammatory cytokines like interleukin-1β (IL-1β) and interleukin-18 (IL-18).

3. Signaling Pathways of NLRs

NLRs are instrumental in detecting various pathogenic and danger signals and initiating downstream signaling pathways. Their central NACHT domain mediates oligomerization, leading to the formation of large complexes that serve as platforms for signaling molecule recruitment. Notable NLRs and their associated signaling pathways include:

1. NOD1 and NOD2: These receptors recognize bacterial peptidoglycans and activate NF-κB signaling pathways, promoting the production of proinflammatory cytokines.

2. NLRP3: Upon activation by a diverse range of stimuli, NLRP3 forms the NLRP3 inflammasome, which leads to caspase-1 activation, cleavage of pro-IL-1β and pro-IL-18, and subsequent release of active cytokines.

3. NLRC4: NLRC4 detects bacterial flagellin and components of the type III secretion system, leading to the assembly of the NLRC4 inflammasome and proinflammatory cytokine release.

4. CIITA (NLRA1): CIITA regulates MHC class II gene expression, playing a critical role in antigen presentation to T cells.

These signaling pathways highlight the diverse functions of NLRs in immune surveillance, inflammation, and host defense.

4. Immune Functions of NLRs

NLRs are integral to the orchestration of immune responses and the maintenance of immune homeostasis. Their functions encompass:

1. Pathogen Detection: NLRs recognize a wide array of pathogenic molecules, including bacterial peptidoglycans, flagellin, and viral RNA, enabling the immune system to respond rapidly to microbial threats.

2. Inflammatory Responses: NLR activation leads to the production of proinflammatory cytokines, such as IL-1β and IL-18, and the initiation of immune responses against infections.

3. Inflammasome Formation: Certain NLRs, like NLRP3 and NLRC4, form inflammasomes, critical multiprotein complexes that activate caspase-1 and trigger the maturation and release of proinflammatory cytokines.

4. Immune Homeostasis: NLRs help maintain immune balance by regulating immune cell differentiation, apoptosis, and cytokine production.

5. Tissue Repair: NLRs play a role in tissue repair and regeneration following infection or injury.

6. Autoinflammatory Diseases: Dysregulation of NLRs can lead to autoinflammatory diseases, characterized by excessive inflammation in the absence of infection.

5. NLRs in Infectious Diseases

NLRs play a central role in host defense against a wide range of infectious agents, including bacteria, viruses, and fungi. For example, NOD1 and NOD2 are crucial for detecting bacterial peptidoglycans, while NLRP3 activation occurs in response to various microbial and danger signals. Understanding the involvement of NLRs in infectious diseases provides insights into host-pathogen interactions and potential therapeutic targets.

6. NLRs in Autoinflammatory Disorders

Aberrant activation of NLRs can lead to autoinflammatory disorders characterized by recurrent episodes of fever, inflammation, and tissue damage. Familial Mediterranean Fever (FMF) and cryopyrin-associated periodic syndromes (CAPS) are examples of conditions where NLRP3 mutations contribute to pathological inflammation. Targeting NLRs presents a promising avenue for treating these disorders by modulating excessive inflammation.

7. NLRs in Cancer

Emerging evidence suggests that NLRs play a role in cancer immunity. They can influence the tumor microenvironment, affecting antitumor immune responses. Strategies that harness NLRs to enhance immune surveillance and target tumors are being explored in cancer immunotherapy.

8. Therapeutic Implications of NLRs

The therapeutic potential of NLRs extends to various areas of medicine. Modulating NLR activity holds promise for addressing infectious diseases, autoinflammatory disorders, and cancer treatment: