Nlrc4: panic button for the calm intestinal phagocyte

It is now well appreciated that phagocytes that inhabit the intestine have a phenotype quite distinct from those of macrophages and dendritic cells isolated or generated from the spleen,

peritoneal cavity, or bone marrow. Perhaps the starkest difference is that intestinal phagocytes are in a state of “inflammatory anergy” in that they do not produce proinflammatory mediators

in response to Toll-like receptor ligands but, rather, serve to promote tolerance to commensal bacteria and food antigens. However, recent findings have shown that these “peace-loving”

cells are in fact equipped with the immune system’s most powerful and highly controlled danger signal—inflammasome-mediated production of interleukin (IL)-1β—and they use it to protect

against invasive flagellated pathogens such as Salmonella typhimurium. Effective use of a hierarchal defense system requires maintaining appropriate control of communications. In the immune

system, this concept manifests in the relative abilities of various cells to produce cytokines that control the movement and activation state of various populations of immune cells. For

example, whereas most cells (including epithelial, endothelial, and other nonimmune cells) are able to produce chemokines that drive localized immune cell recruitment, fewer cell types are

able to generate “master” proinflammatory cytokines such as IL-12 and tumor necrosis factor-a that have more dramatic and systemic effects on host defense and physiology. The use of the

single-most potent cytokine—IL-1β, which can dramatically alter host physiology at the cellular and organismal levels—is further restricted not only by tight control over licensing of its

synthesis but by requiring activation of an entirely distinct signaling pathway—the inflammasome—to process pro-IL-1β into the mature active cytokine.1 Moreover, in contrast to

transcriptionally controlled cytokine production, which can be triggered merely upon extracellular detection of microbial products, inflammasome activation requires intracellular recognition

of select microbial components, thus limiting induction of IL-1β to situations in which bacteria become intracellular. Such multilayered control over Il-1β ought to minimize unwarranted

development of fever and other systemic responses driven by IL-1β without blocking the ability of cells to call for limited immune cell recruitment. Although such multilayered control of

Il-1β production might seem sufficient to protect against inappropriate triggering of systemic inflammation in most locales, given the enormous bacterial load in the intestine, one might

think a logical safeguard might be to not arm intestinal cells with inflammasome machinery altogether. Indeed, intestinal phagocytes (a collective term for intestinal dendritic cells and

macrophages, which are not readily distinguished from each other by classic markers), in stark contrast to other populations of macrophages and dendritic cells, are unresponsive to

Toll-like-receptor agonists.2 Such hyporesponsiveness is thought to be a mechanism to prevent inappropriate triggering of inflammation. Rather, intestinal phagocytes voraciously consume

bacteria and are thought to play a key role in promoting tolerance to such bacteria largely via their constitutive production of anti-inflammatory cytokines such as IL-10 (ref. 3). However,

recent work by Franchi and colleagues4 shows that, although these cells were not deemed trustworthy to call for local security, they are equipped to activate the ultimate danger signal of

inflammasome-mediated IL-1β production. Specifically, the authors observed that intestinal phagocytes were unresponsive to Toll-like-receptor agonists but produced copious levels of mature

IL-1β _ex vivo_ or _in vivo_ in response to pathogenic Salmonella typhimurium. Such IL-1β production required expression of flagellin by the bacteria and host expression of the NLRC4

inflammasome, which is known to recognize flagellin. The fact that activation of intestinal phagocyte NLRC4 required intracellular flagellin was demonstrated by a requirement of a Salmonella

type 3 secretion system, which mediates invasion, and by the ability to overcome this requirement by using the detergent streptolysin-O. To use a military analogy, giving the intestinal

phagocyte (previously considered to be in a state of inflammatory anergy) the ability to produce IL-1β is comparable to preventing a field soldier from radioing his base but enabling him to

alert the entire army if he felt the situation warranted it. Moreover, in contrast to all other known cells, intestinal phagocytes store preformed IL-1β, removing the first layer of control

of expression of this powerful cytokine. The mechanisms that regulate expression and storage of such preformed pro-IL-1β remain to be defined, but they are not dependent on recognition of

microbes because intestinal phagocytes from germ-free mice still stored pro-IL-1β. In any case, intestinal phagocytes not only have the ability to disseminate a red alert but are actually

poised—and seemingly eager—to do so. The fact that intestinal phagocytes can activate the NLRC4 to alter host defense/physiology would seem to provide substantial benefit in the event of

infection by flagellated pathogens, and, indeed, mice deficient in the NLRC4 inflammasome exhibit increased susceptibility to oral Salmonella infections5 (although the extent of the increase

is mouse-strain-dependent). However, equipping the intestinal phagocyte with the immune system’s ultimate alarm signal would seem to invite the possibility of inappropriate inflammation.

Given the strong association of elevated inflammasome cytokines, namely, IL-1β and IL-18, with seemingly inappropriate states of inflammation, particularly in inflammatory disease, this fear

is indeed too frequently realized. Nonetheless, given that phagocytes in the intestine are clearly playing by a number of different rules, it is perhaps wise to presume that NLRC4 is but

one small piece of a puzzle we are only beginning to understand. Andrew T Gewirtz REFERENCES * Dinarello, CA . IL-1: discoveries, controversies and future directions. _Eur. J. Immunol_ 40,

599–606 (2010). Article  CAS  PubMed Central  Google Scholar  * Smythies, L.E . _et al_. Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and

bacteriocidal activity. _J. Clin. Invest_ 115, 66–75 (2005). Article  CAS  PubMed Central  Google Scholar  * Denning, T.L ., Wang, Y.C ., Patel, S.R ., Williams, I.R . & Pulendran, B .

Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17–producing T cell responses. _Nat. Immunol_ 8, 1086–1094 (2007). Article  CAS  PubMed

Central  Google Scholar  * Franchi, L . _et al_. NLRC4-driven production of IL-1beta discriminates between pathogenic and commensal bacteria and promotes host intestinal defense. _Nat.

Immunol_ 13, 449–456 (2012). Article  CAS  PubMed Central  Google Scholar  * Carvalho, F.A . _et al_. Cytosolic flagellin receptor NLRC4 protects mice against mucosal and systemic

challenges. _Mucosal Immunol_ 5, 288–298 (2012). Article  CAS  PubMed Central  Google Scholar  Download references RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE

THIS ARTICLE NLRC4: panic button for the calm intestinal phagocyte. _Mucosal Immunol_ 5, 594–595 (2012). https://doi.org/10.1038/mi.2012.95 Download citation * Published: 25 October 2012 *

Issue Date: November 2012 * DOI: https://doi.org/10.1038/mi.2012.95 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a

shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative