Transitional premonocytes emerge in the periphery for host defense against bacterial infections

Abstract

Circulating Ly6C hi monocytes often undergo cellular death upon exhaustion of their antibacterial effector functions, which limits their capacity for subsequent macrophage differentiation. This shrouds the understanding on how the host replaces the tissue-resident macrophage niche effectively during bacterial invasion to avert infection morbidity. Here, we show that proliferating transitional premonocytes (TpMos), an immediate precursor of mature Ly6C hi monocytes (MatMos), were mobilized into the periphery in response to acute bacterial infection and sepsis. TpMos were less susceptible to apoptosis and served as the main source of macrophage replenishment when MatMos were vulnerable toward bacteria-induced cellular death. Furthermore, TpMo and its derived macrophages contributed to host defense by balancing the proinflammatory cytokine response of MatMos. Consequently, adoptive transfer of TpMos improved the survival outcome of lethal sepsis. Our findings hence highlight a protective role for TpMos during bacterial infections and their contribution toward monocyte-derived macrophage heterogeneity in distinct disease outcomes.

Behind the monocyte’s mystique: uncovering their developmental trajectories and fates

“…Besides HSPCs, committed progenitors such as common DC progenitors (CDPs) [ 138 ], as well as GMPs and MDPs [ 139 ], have been described to migrate into the circulation during infectious settings, with the latter study demonstrating their role in suppressing inflammation. In support of these findings, our research revealed that TpMos gave rise to macrophages that were less inflammatory and transcriptionally distinct from MatMo-derived macrophages, leading to improved sepsis survival [ 133 ]. Since TpMos are the direct precursors of MatMos and the differentiation of these cells occurs along a continuum, it remains challenging to delineate TpMo-derived macrophages from MatMo-derived macrophages through specific markers and future studies would be needed to identify and determine their functions in other inflammatory settings.…”

“…Recently, we have shown that the host is able to overcome the monocyte effector versus replenishment conundrum in an acute bacterial infection model and sepsis setting by mobilizing TpMos, a constitutive proliferating immediate precursor of mature Ly6C hi monocytes (MatMos) located in the BM, into the periphery in a CCR2-independent manner [ 133 ]. Upon migrating into the periphery, TpMos were found to serve as an important source of proliferative monocytes that can readily replenish the macrophage pool.…”

“…Since neutrophils were the main immune cells involved in bacterial clearance [ 155 ], it would be interesting to investigate the impact of neutrophil depletion on monocyte differentiation and its subsequent phenotypes. In light of recent literature that documents distinct BM-imprinted monocytes upon inflammation and mobilization of BM monocyte precursors [ 20 , 29 , 33 , 133 , 140 ], it also remains unclear if these cell types may give rise to different macrophages with inflammatory and anti-inflammatory properties over time. Taken together, the persistence of monocyte-derived cells and their ability to undergo a phenotypic switch over the course of disease relies on a combination of tissue signals ( Fig.…”

Aberrant monocytopoiesis drives granuloma development in sarcoidosis

“…3a ), suggesting that iMOs migrated into the liver and lungs while or before maturing into cMOs. To further study iMO maturation into cMOs, we examined another monocyte maturation marker, CD14, whose expression increases during monocyte maturation into cMOs ( 5 ). We found that ~50% of iMOs in the BM of wild-type mice expressed CD14 ( Fig.…”

“…In mycobacterial infections, TLR2 ligands act on common monocyte progenitors (cMoPs) in the bone marrow (BM) to differentiate into multinucleated giant cells ( 3 , 4 ), suggesting that granuloma development begins early during monocyte/macrophage development. In Escherichia coli infection, premonocytes proliferate in circulation and peripheral organs to replenish the peripheral monocyte/macrophage pool ( 5 ). These findings demonstrated that infections upregulate monocytopoiesis to support peripheral monocyte/macrophage responses.…”