Zone defence – the gut microbiota position macrophages for optimal liver protection

The liver is the largest internal organ and highly vascularized. Two-thirds of its blood flow supplied by portal vein that carries from intestine spleen. Through direct supply gut, large visceral surface bordering peritoneal cavity, target several pathogens can disseminate through into systemic circulation. In this context, it not surprising resident macrophages reside at these two points entry. Preventing dissemination borne one main tasks Kupffer cells (KCs), population in body. These narrow hepatic capillaries, known as sinusoids, where arterial mix percolate before exiting via central veins (Figure 1). sinusoids are delimited single layers parenchymal (hepatocytes), lined a specialized type fenestrated endothelial sinusoidal (LSECs) possessing unusual immune properties.1 KCs located lumen hepatocyte they interact with both LSECs hepatocytes, while same time being exposed to circulating blood.2 They thus strategically effectively sample pathogens, microbial products, food antigens considered key sentinels liver, playing essential roles pathogen clearance host defence during infection.3, 4 Until recently, were sole macrophages. However, we have recently identified another phenotypically distinct macrophage subset positioned second potential site entry: capsule.5 capsular (LCMs) anchored collagen fibers contained capsule form contiguous cellular network contrast embryonically derived, LCMs derived monocytes express high levels CX3CR1. able sense bacteria accessing cavity recruit neutrophils inhibit their dissemination.5 Thus, populations act within liver: guard outer limits survey blood. recent issue Nature, Gola et al.6 further explored defensive role parenchyma. report an additional level complexity surveillance showing gut microbiota unlikely coaching team instructing preferentially localize periportal region, closest inflow, creating KC distribution gradient optimized for efficient surveillance. new findings suggest function location critical role. functional relevance uneven distribution, which authors termed “immune zonation”, be more easily comprehended context architecture characteristics field: liver. parenchyma classically organized repeating hexagonal units lobules center lobule defined each point hexagon corresponds vascular structure, triad, contains vein, artery, bile duct. Blood flows triads vein. Several studies previously established heterogeneous evenly distributed lobule, areas containing two-fold than centrilobular regions.7 Although observations made decades ago, mechanisms governing asymmetrical physiological arrangement have, until now, eluded scientific community. novelty study al. provides mechanistic insight zonation first time. After confirming zonation,6 reveals was weaning disrupted germ free (GF) Myd88-deficient mice, but only partially TLR4-deficient suggesting regulation phenomenon microbiota. Consistent model, co-housing GF mice SPF or treating LPS promoted zonation. Collectively, convincingly imprinted any particular stage development rather result dynamic process depends on sensing products maintain density regions Recent evidence suggests majority significant proportion up bone marrow recruited steady state disease conditions.8 It therefore possible mechanism important position newly monocyte-derived Interestingly, Myd88 deficiency LSECs, resulted disruption signaling primary driver well understood relatively concentrations gut-derived PAMPs under conditions numerous vitro hinted TLR promote production cytokines adhesion molecules;9 however, convincing vivo has been lacking. provide some plays regulating immunological properties also dissected directed KCs. Their reveal LSEC-derived chemokines such CXCL9 CCL17 enriched expressed lower regions,6 along Surprisingly, did regulate chemokine directly altering transcription genes indirectly influencing expression proteins participating formation glycocalyx.6 involved composition organization glycocalyx areas. Based findings, propose Myd88-dependent pathways, response produce components allowing optimal assembly. This turn allows sequestering produced ultimately results consistent other supporting promoting cell migration adhesion.10 While reported previously, highlighted valuable mechanism, certainly worth future exploration. One questions remaining addressed relates gradient. As would PAMPs. circulate might gradually cleared when reach regions, interesting know whether there PAMP sinusoids. Finally, aimed demonstrate significance respect bacterial infection targeting exhibiting showed increased ability capture Listeria monocytogenes prevent spread spleen emphasize randomly tissues, instead pattern selected evolution maximize outcome. Like zonation, compartmentalization tissue specific niches could complementary solution keep strategic locations defence. example, restricted seems reduce entering Intraperitoneal injection mycobacteria lacking 10-fold increase loads comparison LCMs. present, unable compensate lack limitation arises attempted address uptake due spatial differences versus pericentral per basis. isolated livers observed no compared littermate controls.6 observation used design silico approach mathematical modeling binding capacity all equal. model cannot ruled out between microenvironments, oxygen concentration, impart KCs, degrade bacteria; indeed, larger phagocytic KCs.7 lost following isolation culture. question remains unanswered topic worthy investigation. study, elegantly demonstrated unknown links microbiome, production, gradients protection against excess inflammation.6 facilitating conditions. presentation changes inflammatory diseases. For CXCL9-11 CXCL16 unregulated hepatitis C virus (HCV) infection,11 CCL25 sclerosing cholangitis,12 CXCL9, CCL3 CCL4 strongly hepatocellular carcinoma (HCC),10 amounts CCL2 alcohol-related disease.13 will investigate effects diseases control tempting draw parallels margin Both serve similar purpose: close entry parenchyma, pathogens. seem develop generation impaired germ-free mice5; unlike numbers altered recruitment, maintenance remain yet unknown. conclusion, illustrating local defence, solid constant exposure addition composed compartments macrophages, myeloid achieve most response. opens exciting research avenues, highlights undoubtedly discoveries regarding immunity organ. Kieran English: Conceptualization; Writing-original draft; Writing-review & editing. David Bowen: Patrick Bertolino: declare conflicts interest.