Mononuclear phagocytes and the intestinal tolerance

I already wrote a couple of entries about microbiota and the fact that our intestinal commensal bacteria do not stimulate aggressive response from the immune system. Most microorganisms share ligands recognized by innate receptors regardless of whether they are pathogens or symbionts. Therefore the way in which our immune system is viewed to operate – by recognition of conserved molecular patterns by antigen presenting cell populations and ensuing activation of immune response – does not explain well the “microbiota problem”. In fact the question how our body makes a distinction between “attack” vs. “hold on” options at mucosal surfaces still needs unraveling. I have found the report that makes an observation on the subject how intestinal tolerance could be maintained without compromising the need for appropriate response when endangered by infectious organisms. This publication suggests that gut-resident antigen presenting cells may be responsive to the presence of certain pathogen-indicating systems but not to ubiquitously present molecular conserved patterns.

The link: http://www.nature.com/ni/journal/v13/n5/full/ni.2263.html

Authors analyze cytokine release pattern (TNF-α, IL-6 and IL-1β) specific to a population coined as intestinal mononuclear phagocytes (iMPs), which are CD11b+ cells isolated from colonic/cecal lamina propria. Most iMPs bear macrophage marker F4/80. These intestinal antigen presenting cells do not respond by making cytokines to several TLR agonists or commensal bacteria but instead they are able to react to the pathogenic bacterium species – Salmonella. Their cytokine profile is also distinct from bone marrow-derived macrophages as they make only IL-1β but not TNF-α or IL-6. In contrast, bone marrow-derived macrophages produce uniformly TNF-α and IL-6 regardless of provided stimulation (TLR ligands or pathogenic bacterium).

IL-1β response by iMPs does not occur when cells are deficient for NLRC4 (cytosolic Nod-like receptor that forms part of inflammasome complex). It is also absent if Salmonella lacks type 3 secretion system (the apparatus that transports bacterial virulence factors into host cell) or flagellin. Developing this observation investigators provide molecular data that link the cleavage of pro-IL-1β into its active form with inflammasome activity (caspase-1 cleavage). Following the above finding, NLRC4-IL-1β axis is shown to be important for the protection against intestinal pathogenic bacterium in an in vivo model. Experimental infections with Salmonella that approximate human disease (by pretreating mice with streptomycin prior to infection) demonstrate worst survival rates for Nlrc4/ and Il1r/ mutants (however, this effect is strain-dependent as it takes place in BALB/c line but not C57BL/6 strain).

The major conclusion of this publication suggests the existence of a detection network that circumvents TLR signaling and relies on inflammasome activation by features unique to pathogens (like type 3 secretion system). However, I have a question that was not answered in the discussion part. Earlier this year the same group has shown that intestinal macrophages very similar to iMPs  (CD11b+F4/80+CD11c-/low) form the source of IL-1β secretion in response to microbiota (I wrote the entry about that publication few months ago – https://memoryreactivation.wordpress.com/2012/03/11/microbiota-il-1%CE%B2-and-th17/). In the paper I am discussing today it is demonstrated that iMPs do not respond by making IL-1β  to commensal bacteria but can be stimulated only by T3SS-possessing pathogenic bacterium. Could it be caused by anatomical differences as this paper studies colonic/cecal lamina propria population and the former investigates processes in small intestine?

Follow-up note: I have contacted the principal investigator with questions concerning both papers. I received comments confirming that these results were caused by different anatomical locations (small vs. large intestine).

Franchi L, Kamada N, Nakamura Y, Burberry A, Kuffa P, Suzuki S, Shaw MH, Kim YG, & Núñez G (2012). NLRC4-driven production of IL-1β discriminates between pathogenic and commensal bacteria and promotes host intestinal defense. Nature immunology PMID: 22484733

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1 Comment

  1. The intestinal role of NLRC4 « Memory Reactivation

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