Eosinophil-derived CCL-6 impairs hematopoietic stem cell homeostasis

Abstract

Eosinophils (Eos) have been long considered as end-stage effector cells in the hierarchical hematopoietic system. Numerous lines of evidence have suggested that Eos are multifunctional leukocytes with respect to the initiation, propagation and regulation of various inflammatory or immune reactions, especially in allergic diseases. Recent studies have shown that Eos are also required for maintenance of bone marrow plasma cells and differentiation of B cells. However, it remains unclear whether Eos contributes to regulation of hematopoietic stem cell (HSC) homeostasis. Here, we demonstrate that Eos disrupt HSC homeostasis by impairing HSC quiescence and reconstitution ability in wild-type mice following ovalbumin (OVA) challenge and even by causing bone marrow HSC failure and exhaustion in Cd3δ-Il-5 transgenic mice. The impaired maintenance and function of HSCs were associated with Eos-induced redox imbalance (increased oxidative phosphorylation and decreased anti-oxidants levels). More importantly, using mass spectrometry, we determined that CCL-6 is expressed at a high level under eosinophilia. We demonstrate that CCL-6 is Eos-derived and responsible for the impaired HSC homeostasis. Interestingly, blockage of CCL-6 with a specific neutralizing antibody, restored the reconstitution ability of HSCs while exacerbating eosinophilia airway inflammation in OVA-challenged mice. Thus, our study reveals an unexpected function of Eos/CCL-6 in HSC homeostasis.

Eosinophilic inflammation promotes CCL6-dependent metastatic tumor growth

“…In a previous study, overexpression of CCL6 accelerated tumor growth and enhanced local and metastasis spread (15). Similarly, our previous work found that eosinophils secrete CCL6 to promote hematopoietic stem cell proliferation and migration during eosinophilic inflammation (14). Here, we found a dominating role of CCL6 in the cross-talk between eosinophils and tumor cells, strengthening the idea that eosinophil-derived CCL6 directly supports the recruitment of tumor cells, thus promoting tumor metastasis.…”

Stem cell quiescence and its clinical relevance

“…The balance among the adult SC state of quiescence, proliferation, differentiation, and self-renewal can also be regulated through their interactions with nearby cells in the microenvironment, such as eosinophils, mesenchymal stromal cells (MSCs), ECs, macrophages, leukocytes, and immune cells[ 63 - 66 ]. In addition, cell-cell adhesion molecules such as vascular cell adhesion molecule (VCAM)-1, cadherin, and intercellular CAM-1 (ICAM-1) also play important roles in promoting activation of or maintaining quiescence in adult SCs[ 67 - 69 ].…”

“…Eosinophils are multifunctional leukocytes responsible for initiation, enhancement, and control of the inflammatory and immune responses, especially in allergic diseases[ 70 ]. Eosinophils were shown to disrupt hematopoietic SC homeostasis and quiescence via ROS accumulation, which is induced by secretion of chemokine (C-C motif) ligand 6[ 66 ].…”

Eosinophil-derived chemokine (hCCL15/23, mCCL6) interacts with CCR1 to promote eosinophilic airway inflammation

“… 17 Recently, we found that eosinophils disrupt HSC homeostasis by impairing HSC maintenance and mobilization primarily through eosinophil-derived mCCL6. 18 The regulatory effects of eosinophils on stem cells suggest that eosinophils may be involved in the initiation of asthmatic pathology. However, the complex roles of eosinophils and effective factors in allergic asthma are still not completely clear.…”

“… 24 , 25 Our previous findings have shown the potential contribution of eosinophil-derived mCCL6 to HSC impairment in inflammatory airway disease. 18 However, the precise function of mCCL6 is not well understood, and its pathogenic role in allergic asthma remains unknown; similarly, the roles of hCCL23 and hCCL15 in asthma patients remain to be explored.…”