A novel monocyte differentiation pattern in pristane-induced lupus with diffuse alveolar hemorrhage
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Evaluation Summary:
The authors dissect the phenotypes of bone-marrow derived myeloid cells in a murine model of pulmonary vasculitis with relevance to human disease, revealing the association of novel phenotypic subsets associated with lung injury, yet the role of these subsets in regulating or contributing to tissue injury is less clearly determined.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewer remained anonymous to the authors.)
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Abstract
Pristane causes chronic peritoneal inflammation resulting in lupus, which in C57BL/6 mice is complicated by lung microvascular injury and diffuse alveolar hemorrhage (DAH). Mineral oil (MO) also causes inflammation, but not lupus or DAH. Since monocyte depletion prevents DAH, we examined the role of monocytes in the disease. Impaired bone marrow (BM) monocyte egress in Ccr2− /− mice abolished DAH, confirming the importance of monocyte recruitment to the lung. Circulating Ly6C hi monocytes from pristane-treated mice exhibited increased annexin-V staining in comparison with MO-treated controls without evidence of apoptosis, suggesting that pristane alters the distribution of phosphatidylserine in the plasma membrane before or shortly after monocyte egress from the BM. Plasma membrane asymmetry also was impaired in Nr4a1-regulated Ly6C lo/− ‘patrolling’ monocytes, which are derived from Ly6C hi precursors. Patrolling Ly6C lo/− monocytes normally promote endothelial repair, but their phenotype was altered in pristane-treated mice. In contrast to MO-treated controls, Nr4a1-regulated Ly6C lo/− monocytes from pristane-treated mice were CD138 + , expressed more TremL4, a protein that amplifies TLR7 signaling, and exuberantly produced TNFα in response to TLR7 stimulation. TremL4 expression on these novel CD138 + monocytes was regulated by Nr4a1. Thus, monocyte CD138, high TremL4 expression, and annexin-V staining may define an activated/inflammatory subtype of patrolling monocytes associated with DAH susceptibility. By altering monocyte development, pristane exposure may generate activated Ly6C hi and Ly6C lo/− monocytes, contributing to lung microvascular endothelial injury and DAH susceptibility.
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Evaluation Summary:
The authors dissect the phenotypes of bone-marrow derived myeloid cells in a murine model of pulmonary vasculitis with relevance to human disease, revealing the association of novel phenotypic subsets associated with lung injury, yet the role of these subsets in regulating or contributing to tissue injury is less clearly determined.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewer remained anonymous to the authors.)
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Reviewer #1 (Public Review):
The goal of Han and colleagues is to define the role of myeloid cells in diffuse alveolar hemorrhage (DAH), a murine model of pulmonary vasculitis mimicking that found in lupus and induced by peritoneal administration of pristane to B6 mice. The authors characterize circulating and peritoneal myeloid cells in the DAH model, compared to disease-resistant controls, with the principal findings that: 1) DAH is dependent upon monocyte egress from the bone marrow (BM) as opposed to pulmonary resident myeloid cells, as evidenced by its absence in mice deficient in CCR2, and 2) circulating Ly6Clo cells are comprised of 2 subsets, including a CD138+ one development of which is NR4a1 (Nur77) dependent and which expands in association with, but is not required for development of, DAH, and which is akin to circulating …
Reviewer #1 (Public Review):
The goal of Han and colleagues is to define the role of myeloid cells in diffuse alveolar hemorrhage (DAH), a murine model of pulmonary vasculitis mimicking that found in lupus and induced by peritoneal administration of pristane to B6 mice. The authors characterize circulating and peritoneal myeloid cells in the DAH model, compared to disease-resistant controls, with the principal findings that: 1) DAH is dependent upon monocyte egress from the bone marrow (BM) as opposed to pulmonary resident myeloid cells, as evidenced by its absence in mice deficient in CCR2, and 2) circulating Ly6Clo cells are comprised of 2 subsets, including a CD138+ one development of which is NR4a1 (Nur77) dependent and which expands in association with, but is not required for development of, DAH, and which is akin to circulating NR4a1-dependent Ly6Clo cells known to be important for maintenance of vascular integrity, and a Ly6Clo NR4a1- independent one, also previously described, function of which is enigmatic. The former subset also expresses TREML4, expression of which is dependent upon NR4a1 and inflammatory signals. The authors propose that pristane-induced pulmonary vasculitis stimulates production of an inflammatory-induced Ly6Clo monocyte subset important for vascular stability, yet ineffectual is controlling pulmonary vasculitis.
The novel findings are that pulmonary vasculitis is dependent upon BM-derived monocytes, and that the Ly6Clo circulating pool can be divided into two populations based upon NR4a1-developmental dependence and CD138 expression, those that are NR4a1-dependent CD138hi and expanded in vascular injury, and those that are NR4a1-independent CD138lo. Additional strengths of the work are the clear phenotypic analysis with genetic support and correlation to clinical outcome.
Yet, the role of NR4a1-dependent CD138hi cells in vascular injury, either contributing to persistence of damage or ineffectually attempting to resolve it, remains uncertain, as does the apparently unique role of CD138 on these cells and their relationship to the Ly6Clo, NR4a1-independent CD138lo subset and function of the latter. Further dissection of these issues would strengthen the work beyond the clear phenotype-clinical correlations that are made.
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Reviewer #2 (Public Review):
This was an interesting manuscript describing two subsets of Ly6Clo non-classical monocytes in pristane-treated mice, one CD138- and Nr4a1-independent and the other CD138+ and Nr4a1-dependent. The latter are believed to be produced during pristane-induced lung microvascular lung injury in an ineffectual effort to maintain vascular integrity in the face of ongoing endothelial damage. Should this CD138+ Nr4a1-dependent population be a hallmark of vascular injury as the authors suggest, this work could be relevant for many fields. Though most conclusions are supported by data, there are some issues that need to be addressed, mostly relating to the use of mean fluorescence intensity from flow cytometric data as a comparable parameter across multiple tissues to determine relative expression.
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