INFLAMASOME: ACTIVATION AND FUNCTIONS - BIOLOGY - 2024

The inflammasome is a complex composed of several protein domains located in the cell cytosol, whose function is to act as receptors and sensors for the innate immune system. This platform is a defense barrier against the entry of pathogenic microorganisms, which triggers an inflammatory response mediated by the activation of caspase-1.

Several studies in mice indicate the role of the inflammasome in the appearance of serious diseases for public health. For this reason, the elaboration of drugs that affect the inflammasome to improve inflammatory diseases has been studied.

Structure of the Inflamasome. By Haitao Guo, from Wikimedia Commons.

Inflammasomes induce inflammatory, autoimmune, and neurodegenerative diseases, such as multiple sclerosis, Alzheimer's, and Parkinson's. As well as metabolic disorders such as atherosclerosis, type 2 diabetes, and obesity.

Its discovery was made by a group of researchers under the direction of Dr. Tschopp (Martinon 2002). The formation of this structure is due to the induction of the immune response, the purpose of which is to eliminate pathogenic microorganisms or function as a sensor and activator of cellular inflammatory processes.

The assembly of this platform produces the stimulation of procaspase-1 or procaspase-11, which then causes the formation of caspase-1 and caspase-11. These events lead to the production of pro-inflammatory cytokines of the interleukin-1 type, called interleukin-1 beta (IL-1β) and interleukin-18 (IL-18), which come from proIL-1β and proIL-18.

Inflammasomes are important structures, activated by a variety of PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated molecular patterns). They induce the cleavage and release of the pro-inflammatory cytokines interleukin-1 beta (IL-1β) and interleukin-18 (IL-18). They are formed by a nucleotide-binding domain receptor (NLR) or AIM2, ASC, and caspase-1.

Activation of the inflammasome

Inflammasomes are soldiers that appear in the cell cytosol. This type of response is due to the presence of suspicious agents such as PAMPs and DAMPs (Lamkanfi et al, 2014). Activation of cytoplasmic nucleotide-binding domain (NLR) family receptors creates the complex.

Some examples are NLRP1, NLRP3 and NLRC4, as well as other receptors such as the so-called absent in melanoma 2 (AIM2). Within this group, the inflammasome that has been evaluated to a greater degree is NLRP3, due to its great pathophysiological importance in infectious and inflammatory processes. The adapter protein ASC and the effector protein caspase-1 also participate.

Birth of NLRP3

The NLRP3 inflammasome arises in response to a group of signals that can be bacterial, fungal, protozoal, or viral components. As well as other factors such as adenosine triphosphate (ATP), silica, uric acid, certain pore-inducing toxins, among many others (Halle 2008). The structure of NLRP3 is shown in Figure 1.

The NLRP3 inflammasome is activated by various signals, which resemble fireworks, that signal this structure to start working. Examples are the exit of potassium from the cell, the production of oxygen-reactive components of the mitochondria (ROS), the release of cardiolipin, mitochondrial DNA or cathepsin.

Molecular signals related to pathogenic (PAMP) or danger-inducing (DAMP) microorganisms, and pro-inflammatory cytokines (such as TNF-α, IL-1β, IL-6, IL-18), awaken NF-kB. This is the signal for the activation of the NLRP3 inflammasome. It induces the production of NLRP3, pro-IL1β and pro-IL-18, and of pro-inflammatory cytokines such as IL-6, IL-8 and TNF-α, among others.

A subsequent signal tells the NLRP3 inflammasome to assemble so that the NLRP3 / ASC / Pro-caspase-1 complex then appears, informing the caspase-1 that it must be activated. The subsequent step induces pro-IL-1β and pro-IL-18 to mature and IL-1β and IL-18 originate in their active forms.

IL-1β and IL-18 are cytokines that support the inflammatory process. Also, in conjunction with these events, apoptosis and piroptosis may appear.

NLRP3 activation models. By Rjoo317, from Wikimedia Commons.

Functions of the inflammasome

The NLRP3 inflammosome is found in macrophages, monocytes, dendritic cells, and neutrophils. It can be an angel when it attacks infectious agents by activating the inflammatory process. Or on the contrary, a demon that can induce the advancement of various diseases. This is caused by a disorderly and uncontrolled activation when its regulation is affected.

The inflammasome is the main actor in events of the physiology and pathology of some diseases. It has been observed to be involved in ailments associated with inflammation. For example, type 2 diabetes and atherosclerosis (Duewell et al, 2010).

Some studies show that autoinflammatory syndromes are due to problems in the regulation of NLPR3, which causes a very deep and disordered chronic inflammation, apparently associated with the production of IL-1β. With the use of antagonists of this cytokine, the disease reduces its harmful effects on affected individuals (Meinzer et al, 2011).

Role of inflammasomes in the development of diseases

Some research has shown that inflammasomes are important in the damage caused during liver disease. Imaeda et al. (2009) suggest that the NLRP3 inflammasome acts in acetaminophen hepatotoxicity. These studies observe that mice treated with acetaminophen and lack of NLRP3 have lower mortality.

The NLRP3 inflammasome functions as a regulator of intestinal homeostasis by modulating the immune response to the intestinal microbiota. In NLRP3-deficient mice, the amount and type of microbiota changes (Dupaul-Chicoine et al, 2010).

In conclusion, the inflammasome can act on the good side as a molecular platform that attacks infections, as well as on the dark side as an activator of Parkinson's, Alzheimer's, type 2 diabetes mellitus or atherosclerosis, to name just a few.

References

1. Strowig, T., Henao-Mejia, J., Elinav, E. & Flavell, R. (2012). Inflammasomes in health and disease. Nature 481, 278-286.
2. Martinon F, Burns K, Tschopp J. (2002). The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell, 10: 417-426.
3. Guo H, Callaway JB, Ting JP. (2015). Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med, 21 (7): 677-687.
4. Lamkanfi, M. & Dixit, VM (2014). Mechanisms and functions of inflammasomes. Cell, 157, 1013-1022.
5. Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, Fitzgerald KA, Latz E, Moore KJ & Golenbock DT. (2008). The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat. Immunol, 9: 857-865.
6. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, et al. (2010). NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature, 464 (7293): 1357-1361.
7. Meinzer U, Quartier P, Alexandra JF, Hentgen V, Retornaz F, Koné-Paut I. (2011). Interleukin-1 targeting drugs in familial Mediterranean fever: a case series and a review of the literature. Semin Arthritis Rheum, 41 (2): 265-271.
8. Dupaul-Chicoine J, Yeretssian G, Doiron K, Bergstrom KS, McIntire CR, LeBlanc PM, et al. (2010). Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases. Immunity, 32: 367-78. doi: 10.1016 / j.immuni.2010.02.012