Peripheral Macrophages Promote Tissue Regeneration in Zebrafish by Fine-Tuning the Inflammatory Response

Abstract

The role of macrophages during regeneration in zebrafish has been well-documented. Nevertheless, new evidence indicates that zebrafish macrophages are a heterogeneous population of cells, and that they can play different roles during immune responses and in tissue restoration after damage and infection. In this work, we first aimed to classify zebrafish macrophages according to their distribution in the larva during homeostasis and after tissue damage, distinguishing peripheral, and hematopoietic tissue resident macrophages. We discovered differences between the migratory behavior of these two macrophage populations both before and after tissue damage, triggered by the amputation of the tail fin. Further, we found a specific role for peripheral tissue-resident macrophages, and we propose that these cells contribute to tail fin regeneration by down-regulating inflammatory mediators such as interleukin-1b (il1b) and by diminishing reactive oxygen species (ROS) in the damage site. Our work suggests that specific macrophage populations recruited after tissue damage in zebrafish larvae can display different functions during both inflammation and tissue regeneration.

Determining macrophage versus neutrophil contributions to innate immunity using larval zebrafish

“…Overall, these studies suggest that although early expression of these proinflammatory genes is required for efficient repair, their expression must be downregulated to promote late healing and implicate macrophages in both early and late healing phases (Tsarouchas et al, 2018;Hasegawa et al, 2017;Nguyen-Chi et al, 2017). Work in a csf1ra mutant identified peripheral macrophages as the cells responsible for downregulating il1b expression (Morales and Allende, 2019). One function of tnfa signaling may be to support the proliferation of cells in the blastema (Box 3) (Nguyen-Chi et al, 2017).…”

“…il34 mutants therefore also have fewer microglia (Wu et al, 2018;Kuil et al, 2019). Some tissue-resident macrophages also come from these early-arising cells, and csf1ra −/− or il34 crispant (Box 3) larvae have fewer peripheral macrophages with fewer protrusions that respond poorly to tail fin injury (Kuil et al, 2019;Wu et al, 2018;Pagán et al, 2015;Morales and Allende, 2019).…”

“…Multiple recent papers have focused on the role of macrophages in modulating the immune environment at an injury site, especially through regulation of the pro-inflammatory cytokines il1b and tnfa (Box 3) (Tsarouchas et al, 2018;Morales and Allende, 2019;Nguyen-Chi et al, 2017;Hasegawa et al, 2017). These proinflammatory mediators are turned on early in the wound response and downregulated in later stages of repair (Tsarouchas et al, 2018;Hasegawa et al, 2017).…”

“…A second issue is that wounding leads to a significant level of cell death, and a major role of macrophages is to phagocytose dead cells and debris (Tabas, 2010). Several studies documented an increase in the number of dead cells at the wound and in the blastema after tail fin amputation in macrophage-deficient larvae (Hasegawa et al, 2015(Hasegawa et al, , 2017Loynes et al, 2018;Morales and Allende, 2019). However, the interpretation of this observation has differed, with studies concluding either that macrophages produce a signal to promote the survival of these cells (Hasegawa et al, 2015(Hasegawa et al, , 2017 or that these are cells that would normally be cleared by phagocytic macrophages (Loynes et al, 2018).…”

Failure to clear developmental apoptosis contributes to the pathology of RNASET2-deficient leukoencephalopathy

“…Figure 9). To determine if loss of rnaset2 affects all macrophages, we assessed macrophage innate immune function by studying responses to tissue damage induced by caudal tail fin transection (Morales and Allende, 2019). No difference was identified in macrophage recruitment to the wound site at 24hpi ( Figure 4A,F,G), suggesting that loss of rnaset2 disrupts microglial function in the CNS without affecting the innate immune responses in the periphery.…”