Slit3 secreted from M2-like macrophages increases sympathetic activity and thermogenesis in adipose tissue

Abstract

Beiging of white adipose tissue (WAT) is capable of adaptive thermogenesis and dissipating energy. The beiging processes have been associated with the increase of anti-inflammatory M2 macrophages, however the function of M2 macrophage on beiging and the underlying mechanism are not fully understood. Here we identified a macrophage cytokine Slit3 by analyzing the transcriptome of M2 macrophages collected with FACS in inguinal WAT (iWAT) of mice after cold exposure. Once released from macrophages, Slit3 bound to the ROBO1 receptor on sympathetic neuron and activated tyrosine hydrolase (TH) through PKA and CaMKⅡ signaling, and thus stimulated norepinephrine (NE) synthesis and release. NE acts on adipocytes and stimulate thermogenesis. Adoptive transfer of Slit3-overexpressing M2 macrophages to iWAT depot acquired local adipocytes with beiging phenotype and enhanced thermogenesis. In addition, mice bearing the myeloid inactivation of Slit3 were cold intolerant and gained more weight due to the lowered metabolic rate.Collectively, we demonstrate Slit3 is a macrophage cytokine and promotes beiging and thermogenesis through intensifying the sympathetic nerve function. As the expanded M2 macrophages are integral cell population in adipose tissue, the macrophage-Slit3-sympathetic neuron-adipocyte axis assures the long-term cold adaption.

The Adipose Tissue Macrophages Central to Adaptive Thermoregulation

“…Instead, it was linked to sustaining sympathetic innervation and adaptive thermogenesis at a steady-state for homeostasis. As discussed, alternatively activated macrophages have also been reported to involve sympathetic nerve outgrowth in subcutaneous WAT during cold adaptation ( 16 , 60 ). Therefore, available evidence indicates that a discrete subpopulation of ATMs may reshape local sympathetic innervation to mediate energy expenditure and maintain metabolic homeostasis.…”

“…A recent study provided a novel aspect of M2 macrophage-dependent catecholamine secretion and beiging by discovering the mechanism by which M2 macrophages enhanced the local SNS activation in subcutaneous WAT upon cold exposure. Slit guidance ligand 3 (SLIT3) secreted from M2 macrophages induced sympathetic innervation and TH activation by binding to sympathetic neurons via roundabout guidance receptor 1 (ROBO1), thereby promoting NE synthesis and beiging to sustain adaptive thermogenesis ( 16 ). Consistent with this notion, an independent study found that IL-25-induced M2 macrophage polarization increased outgrowth of sympathetic nerves in subcutaneous WAT ( 60 ).…”

The shades of grey in adipose tissue reprogramming

“…There is emerging evidence regarding the non-canonical functions of AT immune cells beyond immune-modulation, including angiogenesis and browning/beiging [ 105 , 113–115 ]. In addition to their anti-inflammatory properties, the M2-like ATMs are activated during a cold challenge to secrete the signalling protein SLIT3, which promotes the AT sympathetic nerve fibres to release norepinephrine and to nudge the white adipocytes into thermogenic adipocytes [ 116 ]. Similarly, tissue-resident γδ T cells, which are required for T regulatory cell accumulation, have crucial involvement in adaptive thermogenesis and brown AT innervation [ 58 , 117 ].…”

Neuroendocrine regulations in tissue-specific immunity: From mechanism to applications in tumor

“…Slit3 is a macrophage cytokine secreted by ATM. It binds to the ROBO1 receptor to stimulate Ca2+/calmodulin-dependent protein kinase II signaling and NE release, which enhances adipocyte thermogenesis ( Wang et al, 2021 ). Additionally, MMs regulate peristaltic activity of the colon by secreting bone morphogenetic protein 2 (BMP2), which activates the expression of BMP receptor on enteric neurons.…”