The intestinal immune system discriminates between tolerance toward the commensal microflora and robust responses to pathogens. Maintenance of this critical balance is attributed to mucosal dendritic cells (DCs) residing in organized lymphoid tissue and dispersed in the subepithelial lamina propria. In situ parameters of lamina propria DCs (lpDCs) remain poorly understood. Here, we combined conditional cell ablation and precursor-mediated in vivo reconstitution to establish that lpDC subsets have distinct origins and functions. CD103(+) CX(3)CR1(-) lpDCs arose from macrophage-DC precursors (MDPs) via DC-committed intermediates (pre-cDCs) through a Flt3L growth-factor-mediated pathway. CD11b(+) CD14(+) CX(3)CR1(+) lpDCs were derived from grafted Ly6C(hi) but not Ly6C(lo) monocytes under the control of GM-CSF. Mice reconstituted exclusively with CX(3)CR1(+) lpDCs when challenged in an innate colitis model developed severe intestinal inflammation that was driven by graft-derived TNF-alpha-secreting CX(3)CR1(+) lpDCs. Our results highlight the critical importance of the lpDC subset balance for robust gut homeostasis.
The CX 3 C chemokine family is composed of only one member, CX 3 CL1, also known as fractalkine, which in mice is the sole ligand of the G proteincoupled, 7-transmembrane receptor CX 3 CR1. Unlike classic small peptide chemokines, CX 3 CL1 is synthesized as a membrane-anchored protein that can promote integrin-independent adhesion. Subsequent cleavage by metalloproteases, either constitutive or induced, can generate shed CX 3 CL1 entities that potentially have chemoattractive activity. To study the CX 3 C interface in tissues of live animals, we generated transgenic mice (CX 3 CL1 cherry :CX 3 CR1 gfp ), which express red and green fluorescent reporter genes under the respective control of the CX 3 CL1 and CX 3 CR1 promoters. Furthermore, we performed a structure/function analysis to differentiate the in vivo functions of membranetethered versus shed CX 3 CL1 moieties by comparing their respective ability to correct established defects in macrophage function and leukocyte survival in IntroductionChemokine (CX 3 C motif) ligand 1 (CX 3 CL1), also known as fractalkine or neurotactin, 1,2 and its receptor CX 3 CR1 3 have been assigned their own CX 3 C chemokine family. This classification is based on the 3 amino acid gap between its N-terminal cysteines in CX 3 CL1, with no spacing in CC chemokines and only one intervening amino acid in CXC chemokines. 4 CX 3 CL1 is furthermore structurally unique in that it is synthesized as a type I transmembrane protein with the CX 3 C chemokine domain presented on an extended stalk. 1,2 Both CX 3 CL1 and CX 3 CR1 are widely expressed throughout the organism; but in given tissues, expression is often highly cell type-specific. Taking advantage of mice that harbor a targeted replacement of the CX 3 CR1 gene by a GFP reporter, 5 we could, for instance, show that CX 3 CR1 expression in the brain is restricted to microglia. CX 3 CR1 expression in the gut was found limited to lamina propria macrophages and CX 3 CR1 expression in the blood is largely restricted to monocytes, which are uniform CX 3 CR1 positive, albeit with discrete expression levels. 6 CX 3 CR1 is furthermore expressed by macrophage/ dendritic cell precursors, 7 various dendritic cell (DC) progenitors, a nonclassic CD8␣ ϩ DC subset, 8 and plasmacytoid DCs. Aside from the prominent expression in the mononuclear myeloid compartment, CX 3 CR1 receptor expression has been reported for an NK cell subset 3,9 and certain T-cell populations. 3,10,11 The in vivo expression pattern of the ligand CX 3 CL1 remains less well defined and controversial 12 but has been reported for neurons, 13 intestinal epithelium, 14 and inflamed endothelium. 2 Notably, in humans eotaxin-3/CC chemokine ligand 26 was recently reported to be a functional ligand for CX 3 CR1 15 ; in mice, the CCL26 gene, however, is a pseudogene.The analysis of CX 3 C receptor and ligand knockout mice 5,16 has revealed a number of phenotypes resulting from the lack of CX 3 CR1/ CX 3 CL1 interactions. [17][18][19][20] However, in-depth knowledge of the physiologic rol...
The lamina propria that underlies and stabilizes the gut lining epithelium is densely populated with strategically located mononuclear phagocytes. Collectively, these lamina propria macrophages and dendritic cells (DC) are believed to be crucial for tissue homeostasis as well as the innate and adaptive host defense. Lamina propria DC were recently shown to gain direct access to the intestinal lumen by virtue of epithelium-penetrating dendrites. However, the role of these structures in pathogen uptake remains under debate. In this study, we report that entry of a noninvasive model pathogen (Aspergillus fumigatus conidia) into the murine small intestinal lamina propria persists in the absence of either transepithelial dendrites or lamina propria DC and macrophages. Our results suggest the existence of multiple pathogen entry pathways and point at the importance of villus M cells in the uptake of gut lumen Ags. Interestingly, transepithelial dendrites seem altogether absent from the small intestine of BALB/c mice suggesting that the function of lamina propria DC extensions resides in their potential selectivity for luminal Ags, rather than in general uptake or gut homeostasis.
Inhalational anthrax is a life-threatening infectious disease of considerable concern, especially because anthrax is an emerging bioterrorism agent. The exact mechanisms leading to a severe clinical form through the inhalational route are still unclear, particularly how immobile spores are captured in the alveoli and transported to the lymph nodes in the early steps of infection. We investigated the roles of alveolar macrophages and lung dendritic cells (LDC) in spore migration. We demonstrate that alveolar macrophages are the first cells to phagocytose alveolar spores, and do so within 10 min. However, interstitial LDCs capture spores present in the alveoli within 30 min without crossing the epithelial barrier suggesting a specific mechanism for rapid alveolus sampling by transepithelial extension. We show that interstitial LDCs constitute the cell population that transports spores into the thoracic lymph nodes from within 30 min to 72 h after intranasal infection. Our results demonstrate that LDCs are central to spore transport immediately after infection. The rapid kinetics of pathogen transport may contribute to the clinical features of inhalational anthrax.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.