Inhibition of immune checkpoints prevents injury-induced heterotopic ossification

Chen Kan; Jiazhao Yang; Ding Na; Yuanhong Xu; Baixia Yang; Haodong Zhao; Huadong Lu; Yuyun Li; Keqin Zhang; Tammy L. McGuire; John A. Kessler; Lixin Kan

doi:10.1038/s41413-019-0074-7

Inhibition of immune checkpoints prevents injury-induced heterotopic ossification

Chen Kan, Jiazhao Yang, Ding Na, Yuanhong Xu, Baixia Yang, Haodong Zhao, Huadong Lu, Yuyun Li, Keqin Zhang, Tammy L. McGuire, John A. Kessler^*, Lixin Kan

^*Corresponding author for this work

Neurology

Research output: Contribution to journal › Article › peer-review

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Abstract

Heterotopic ossification (HO), true bone formation in soft tissue, is closely associated with abnormal injury/immune responses. We hypothesized that a key underlying mechanism of HO might be injury-induced dysregulation of immune checkpoint proteins (ICs). We found that the earliest stages of HO are characterized by enhanced infiltration of polarized macrophages into sites of minor injuries in an animal model of HO. The non-specific immune suppressants, Rapamycin and Ebselen, prevented HO providing evidence of the central role of the immune responses. We examined the expression pattern of ICs and found that they are dysregulated in HO lesions. More importantly, loss of function of inhibitory ICs (including PD1, PD-L1, and CD152) markedly inhibited HO, whereas loss of function of stimulatory ICs (including CD40L and OX-40L) facilitated HO. These findings suggest that IC inhibitors may provide a therapeutic approach to prevent or limit the extent of HO.

Original language	English (US)
Article number	33
Journal	Bone Research
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s41413-019-0074-7
State	Published - Dec 1 2019

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism
Histology
Physiology

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10.1038/s41413-019-0074-7

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title = "Inhibition of immune checkpoints prevents injury-induced heterotopic ossification",

abstract = "Heterotopic ossification (HO), true bone formation in soft tissue, is closely associated with abnormal injury/immune responses. We hypothesized that a key underlying mechanism of HO might be injury-induced dysregulation of immune checkpoint proteins (ICs). We found that the earliest stages of HO are characterized by enhanced infiltration of polarized macrophages into sites of minor injuries in an animal model of HO. The non-specific immune suppressants, Rapamycin and Ebselen, prevented HO providing evidence of the central role of the immune responses. We examined the expression pattern of ICs and found that they are dysregulated in HO lesions. More importantly, loss of function of inhibitory ICs (including PD1, PD-L1, and CD152) markedly inhibited HO, whereas loss of function of stimulatory ICs (including CD40L and OX-40L) facilitated HO. These findings suggest that IC inhibitors may provide a therapeutic approach to prevent or limit the extent of HO.",

author = "Chen Kan and Jiazhao Yang and Ding Na and Yuanhong Xu and Baixia Yang and Haodong Zhao and Huadong Lu and Yuyun Li and Keqin Zhang and McGuire, {Tammy L.} and Kessler, {John A.} and Lixin Kan",

note = "Funding Information: We appreciate the help from many other members of the Kessler laboratory. This work was supported by NIH grant RO1 AR066539 (to J.A.K.). L.K. was supported in part by National Natural Science Foundation of China (81472087) and Natural Science Foundation of Anhui province (1508085MC45). Publisher Copyright: {\textcopyright} 2019, The Author(s).",

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doi = "10.1038/s41413-019-0074-7",

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AU - Kan, Chen

AU - Yang, Jiazhao

AU - Na, Ding

AU - Xu, Yuanhong

AU - Yang, Baixia

AU - Zhao, Haodong

AU - Lu, Huadong

AU - Li, Yuyun

AU - Zhang, Keqin

AU - McGuire, Tammy L.

AU - Kessler, John A.

AU - Kan, Lixin

N1 - Funding Information: We appreciate the help from many other members of the Kessler laboratory. This work was supported by NIH grant RO1 AR066539 (to J.A.K.). L.K. was supported in part by National Natural Science Foundation of China (81472087) and Natural Science Foundation of Anhui province (1508085MC45). Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Heterotopic ossification (HO), true bone formation in soft tissue, is closely associated with abnormal injury/immune responses. We hypothesized that a key underlying mechanism of HO might be injury-induced dysregulation of immune checkpoint proteins (ICs). We found that the earliest stages of HO are characterized by enhanced infiltration of polarized macrophages into sites of minor injuries in an animal model of HO. The non-specific immune suppressants, Rapamycin and Ebselen, prevented HO providing evidence of the central role of the immune responses. We examined the expression pattern of ICs and found that they are dysregulated in HO lesions. More importantly, loss of function of inhibitory ICs (including PD1, PD-L1, and CD152) markedly inhibited HO, whereas loss of function of stimulatory ICs (including CD40L and OX-40L) facilitated HO. These findings suggest that IC inhibitors may provide a therapeutic approach to prevent or limit the extent of HO.

AB - Heterotopic ossification (HO), true bone formation in soft tissue, is closely associated with abnormal injury/immune responses. We hypothesized that a key underlying mechanism of HO might be injury-induced dysregulation of immune checkpoint proteins (ICs). We found that the earliest stages of HO are characterized by enhanced infiltration of polarized macrophages into sites of minor injuries in an animal model of HO. The non-specific immune suppressants, Rapamycin and Ebselen, prevented HO providing evidence of the central role of the immune responses. We examined the expression pattern of ICs and found that they are dysregulated in HO lesions. More importantly, loss of function of inhibitory ICs (including PD1, PD-L1, and CD152) markedly inhibited HO, whereas loss of function of stimulatory ICs (including CD40L and OX-40L) facilitated HO. These findings suggest that IC inhibitors may provide a therapeutic approach to prevent or limit the extent of HO.

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Inhibition of immune checkpoints prevents injury-induced heterotopic ossification

Abstract

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