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A Critical Role of SHP-1 in Regulation of Type 2 Inflammation in the Lung

¹ Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, Maryland; ² Section of Pulmonary and Critical Care Medicine and Department of Pathology, Yale University School of Medicine, New Haven, Connecticut; and ³ Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom

Correspondence and requests for reprints should be addressed to Zhou Zhu, M.D., Ph.D., Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle/1A.2, Baltimore, MD 21224. E-mail: zzhu{at}jhmi.edu

Asthma is a chronic inflammatory disorder of the airways. Type 2 T helper (Th) cell–dominated inflammation in the lung is a hallmark of asthma. Src homology 2 domain–containing protein tyrosine phosphatase (SHP)-1 is a negative regulator in the signaling pathways of many growth factor and cytokine receptors. However, a direct role of SHP-1 in the IL-4/IL-13 signaling pathway has not been established. In this study, we sought to define the function of SHP-1 in the lung by characterizing the pulmonary inflammation of viable motheaten (mev) mice, and to investigate the molecular mechanisms involved. Pulmonary histology, physiology, and cytokine expression of mev mice were analyzed to define the nature of the inflammation, and the gene-deletion approach was used to identify critical molecules involved. In mev mice, we observed spontaneous Th2-like inflammatory responses in the lung, including eosinophilia, mucus metaplasia, airway epithelial hypertrophy, pulmonary fibrosis, and increased airway resistance and airway hyperresponsiveness. The pulmonary phenotype was accompanied by up-regulation of Th2 cytokines and chemokines. Selective deletion of IL-13 or signal transducer and activator of transcription 6, key genes in the Th2 signaling pathway, significantly reduced, but did not completely eliminate, the inflammation in the lung. These findings suggest that SHP-1 plays a critical role in regulating the IL-4/IL-13 signaling pathway and in maintaining lung homeostasis.

Key Words: Src homology 2 domain–containing protein tyrosine phosphatase-1 • protein tyrosine phosphatase • motheaten mouse • type 2 T helper cell inflammation • lung

CLINICAL RELEVANCE This study revealed a critical role of the phosphatase Src homology 2 domain–containing protein tyrosine phosphatase-1 in maintaining lung homeostasis and in regulating type 2 T helper cell inflammation in the lung. More attention should be given to the process of negative regulation in understanding and controlling pulmonary inflammation.

 

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