Self-Tolerance of Vascular Tissues Is Broken Down by Vascular Dendritic Cells in Response to Systemic Inflammation to Initiate Regional Autoinflammation.

Li Sun,Yuekang Xu,Andrew M Lew,Wenjie Zhang,Lin Zhao,Yanfang Zhao,Fengge Wang

doi:10.3389/fimmu.2022.823853

Abstract

The correlation of infections with vascular autoinflammatory diseases such as vasculitis and atherosclerosis has been long recognized, and progressive inflammation with the formation of tertiary lymphoid organs in arterial adventitia intensively studied, the immunological basis of the nondiseased vasculatures that predispose to subsequent vascular autoimmunity during inflammation, however, is not well characterized. Here, we investigated the vascular immunity in situ of steady-state C57BL/6 mice and found that healthy vascular tissues contained a comprehensive set of immune cells with relatively higher proportion of innate components than lymphoid organs. Notably, a complete set of dendritic cell (DC) subsets was observed with monocyte-derived DCs (moDCs) constituting a major proportion; this is in contrast to moDCs being considered rare in the steady state. Interestingly, these vascular DCs constitutively expressed more suppressive factors with cDC1 for PD-L1 and moDCs for IL-10; this is concordant with the inhibitive phenotype of T cells in normal vascular tissues. The immunotolerant state of the vascular tissues, however, was readily eroded by systemic inflammation, demonstrated by the upregulation of proinflammatory cytokines and enhanced antigen presentation by vascular DCs to activate both cellular and humoral immunity in situ, which ultimately led to vascular destruction. Different vascular DC subsets elicited selective effects: moDCs were potent cytokine producers and B-cell activators, whereas cDCs, particularly, cDC1, were efficient at presenting antigens to stimulate T cells. Together, we unveil regional immunological features of vascular tissues to explain their dual facets under physiological versus pathological conditions for the better understanding and treatment of cardiovascular autoinflammation.

Highlights

As the first line of defense against the invasion of foreign pathogens, leukocytes are often present at peripheral barrier tissues, including the skin, gastrointestinal tract, and respiratory tract
The proportion of dendritic cell (DC) and macrophages within the immune cells were higher in the aortic blood vascular (BV) tissues (Figure 1B) whereas granulocytes were similar in these two organs
Even though monocyte-derived DCs (moDCs) are relatively rare in the steady state [10, 27, 28], we found that the predominant vascular DC type was moDCs; whereas, it is the rarest DC type in the spleen (Figure 1D)

Summary

Introduction

As the first line of defense against the invasion of foreign pathogens, leukocytes are often present at peripheral barrier tissues, including the skin, gastrointestinal tract, and respiratory tract. In response to infectious challenge, innate immune cells respond quickly often overcoming the invaders; in case the pathogens persist, innate cells alert the adaptive immune cells, which are most abundant in secondary lymphoid organs (SLOs) such as the spleen, lymph nodes, and Peyer’s patches Beyond these tissues, immune cells may reside in, albeit in rare numbers, deep nonbarrier tissues such as adipose, meninges, uterus, and cardiovascular tissues. Leukocytes may gather in the blood vessels in expandable adventitial cuffs via interstitial fluid flow constitutively or chemotactically [3]. Such above pathways could possibly constitute their own unique immune network and avail leucocytic infiltration within vascular walls as early as the first year of childhood [4]

Methods

Results

Conclusion