Pulmonary Haptoglobin and CD163 Are Functional Immunoregulatory Elements in the Human Lung

Abstract

Background: The acute-phase protein haptoglobin (Hp) and its receptor CD163 serve as immunomodulators and possess anti-inflammatory besides antioxidant functions. Objectives: To further understand the role of the recently described pulmonary Hp (pHp) and its receptor CD163 in case of inflammation and infection, pHp and CD163 were investigated on mRNA and protein level to gain insight into the cellular events taking place upon stimulation with the inflammatory mediators LPS, Pam3, cytokine IL-6 and dexamethasone, and upon infection with respiratory pathogens (Haemophilus influenzae, Streptococcuspneumoniae and Chlamydia pneumoniae) by use of a human ex vivo tissue culture model and cell cultures of A549 and alveolar epithelial cells type II. In addition, pHp and CD163 expression in COPD and sarcoidosis was assessed. Methods: We conducted experiments using 942 ex vivo cultured lung samples applying immunohistochemistry, immunocytochemistry, in situ hybridization, immunofluorescence, real-time PCR, RT-PCR, slot and Western immunoblot analyses with tissue lysates and culture supernatants as well as ELISA and cytometric bead array analyses. Results: This study describes for the first time the expression, regulation and secretion of pHp and its receptor CD163 in the human lung. The release of soluble mediators from A549 cell line and human monocyte-derived macrophages was observed indicating that Hp differentially activates the release of soluble mediators and major chemoattractants. Conclusions: The findings indicate a native function of pHp and CD163 as functional pulmonary defense elements due to local expression, regulation and secretion during lung infection and as part of the inflammatory immune response of the respiratory system.

Clinical significance of sCD163 and its possible role in asthma

“…CD163 may function as a pulmonary defense element, as suggested by its local expression in the lungs, and its secretion during lung infection and as part of inflammatory respiratory responses (98). Cell surface expression of CD163 on alveolar macrophages is reduced in human subjects with asthma, which suggests that CD163 may participate in the regulation of airway inflammatory responses in the lung (85).…”

Genetic Variation in the Scavenger Receptor MARCO and Its Association with Chronic Obstructive Pulmonary Disease and Lung Infection in 10,604 Individuals

“…However, this mutation did not associate with other infectious endpoints, and since the finding was based on a relatively low number of individuals it could represent a chance finding rather than a real phenomenon. On the other hand, studies support that MARCO [28,29] and other scavenger receptors [28,30,31,32] could be related to sepsis. The in vivo expression of MARCO is normally restricted to distinct populations of macrophages in the spleen and lymph nodes in mice.…”

Pulmonary haptoglobin (pHp) is part of the surfactant system in the human lung

“…We recently reported that the plasma protein haptoglobin (Hp) is also synthesized and expressed in the human lung [1]. We described expression of Hp-protein in Lung cancer (mainly in Adenocarcinomas of the lung), Alveolar Epithelial Cells type II (AECII), alveolar macrophages and bronchial epithelia.…”

“…Cell specific synthesis of pHp was addressed by RNA-in situ hybridization, which revealed pHp transcription in AECII and alveolar macrophages [1]. A possible secretion of pHp by pulmonary cells has been addressed utilizing human lung explants and A549 cells.…”

“…We showed that pHp is indeed secreted by lung tissues and A549 cells. This secretion depends on different stimuli like LPS, IL6, Pam3Cys-Ser-(Lys)4, and, interestingly, dexamethasone [1]. Secretion of pHp happens comparably fast, it was measurable in supernatants already after ten minutes of stimulation, which is by far faster than the most other immuno-regulatory systems in the lung e.g.…”