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Physiopathology of necrobiotic xanthogranuloma with monoclonal gammopathy.

Szalat R, Pirault J, Fermand JP, Carrié A, Saint-Charles F, Olivier M, Robillard P, Frisdal E, Villard EF, Cathébras P, Bruckert E, Chapman MJ, Giral P, Guerin M, Lesnik P, Le Goff W - J. Intern. Med. (2014)

Bottom Line: This accumulation was due in part to a significant reduction in the HDL capacity to promote cholesterol efflux from macrophages, which was not found in the case of NX.However, patients with NXG were distinguished by elevated levels of IL-15 and a marked increase in the rate of intermediate CD14++CD16+ monocytes.This study revealed that NXG is characterized by impaired macrophage lipid homeostasis associated with a systemic inflammatory profile that may result from the interaction of MIg and lipoproteins.

View Article: PubMed Central - PubMed

Affiliation: Département d'immunologie Clinique, Hôpital Saint Louis, Paris, France; EA3963, Université Paris 7 Denis Diderot, INSERM, IFR105, Institut Universitaire d'Hématologie, Paris, France.

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Proposed molecular and cellular mechanisms for the appearance of skin lesions in patients with NX and NXG. Low levels of anti-inflammatory HDL-C (apoA-I) were associated with increased expression of chemokine receptor CCR2 in circulating monocytes and elevated levels of chemokines (MCP-1, IL-8, MIP-1α) and adhesion molecules (VCAM-1, ICAM-1), which might favour monocyte recruitment and homing to skin in patients with NX and NXG. This effect might be exacerbated in the case of NXG due to the presence of a high proportion of intermediate CD14++CD16+ monocytes. Moreover, increased levels of soluble receptors (sIL-6R, sTNFRI and TNFRII), which were also inversely correlated with plasma HDL-C (apoA-I) levels, contributed to the ‘xanthoma inflammatory profile’ observed in patients with NX and NXG. Although serum from both NX and NXG promoted cholesterol accumulation in macrophages, the appearance of foam cells in NXG likely also resulted from the impaired capacity of HDL particles (HDL3c) to promote macrophage cholesterol efflux. In addition, the presence of immune complexes (IgG anti-lipoproteins) that might enter into macrophage through phagocytosis via scavenger or Fcγ receptors may also contribute to foam-cell formations in both NXG and NX. Finally, the differential levels of EGF, IL-15 and IFNγ observed in NX and NXG subjects could provide some preliminary clues to help explain the mechanisms underlying the distinct clinical patterns that characterize NX and NXG.
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fig05: Proposed molecular and cellular mechanisms for the appearance of skin lesions in patients with NX and NXG. Low levels of anti-inflammatory HDL-C (apoA-I) were associated with increased expression of chemokine receptor CCR2 in circulating monocytes and elevated levels of chemokines (MCP-1, IL-8, MIP-1α) and adhesion molecules (VCAM-1, ICAM-1), which might favour monocyte recruitment and homing to skin in patients with NX and NXG. This effect might be exacerbated in the case of NXG due to the presence of a high proportion of intermediate CD14++CD16+ monocytes. Moreover, increased levels of soluble receptors (sIL-6R, sTNFRI and TNFRII), which were also inversely correlated with plasma HDL-C (apoA-I) levels, contributed to the ‘xanthoma inflammatory profile’ observed in patients with NX and NXG. Although serum from both NX and NXG promoted cholesterol accumulation in macrophages, the appearance of foam cells in NXG likely also resulted from the impaired capacity of HDL particles (HDL3c) to promote macrophage cholesterol efflux. In addition, the presence of immune complexes (IgG anti-lipoproteins) that might enter into macrophage through phagocytosis via scavenger or Fcγ receptors may also contribute to foam-cell formations in both NXG and NX. Finally, the differential levels of EGF, IL-15 and IFNγ observed in NX and NXG subjects could provide some preliminary clues to help explain the mechanisms underlying the distinct clinical patterns that characterize NX and NXG.

Mentions: In conclusion, our present findings are integrated schematically in Fig.5. Herein, we report that NXG is characterized by an abnormal HDL phenotype associated with a unique inflammatory pattern, the preponderance of a specific monocyte subset and an impaired macrophage cholesterol homeostasis, probably due to interactions between MIg and lipoproteins. Although NXG is a relatively rare condition, our results contribute to the understanding of the cellular mechanisms involved in lipid accumulation.


Physiopathology of necrobiotic xanthogranuloma with monoclonal gammopathy.

Szalat R, Pirault J, Fermand JP, Carrié A, Saint-Charles F, Olivier M, Robillard P, Frisdal E, Villard EF, Cathébras P, Bruckert E, Chapman MJ, Giral P, Guerin M, Lesnik P, Le Goff W - J. Intern. Med. (2014)

Proposed molecular and cellular mechanisms for the appearance of skin lesions in patients with NX and NXG. Low levels of anti-inflammatory HDL-C (apoA-I) were associated with increased expression of chemokine receptor CCR2 in circulating monocytes and elevated levels of chemokines (MCP-1, IL-8, MIP-1α) and adhesion molecules (VCAM-1, ICAM-1), which might favour monocyte recruitment and homing to skin in patients with NX and NXG. This effect might be exacerbated in the case of NXG due to the presence of a high proportion of intermediate CD14++CD16+ monocytes. Moreover, increased levels of soluble receptors (sIL-6R, sTNFRI and TNFRII), which were also inversely correlated with plasma HDL-C (apoA-I) levels, contributed to the ‘xanthoma inflammatory profile’ observed in patients with NX and NXG. Although serum from both NX and NXG promoted cholesterol accumulation in macrophages, the appearance of foam cells in NXG likely also resulted from the impaired capacity of HDL particles (HDL3c) to promote macrophage cholesterol efflux. In addition, the presence of immune complexes (IgG anti-lipoproteins) that might enter into macrophage through phagocytosis via scavenger or Fcγ receptors may also contribute to foam-cell formations in both NXG and NX. Finally, the differential levels of EGF, IL-15 and IFNγ observed in NX and NXG subjects could provide some preliminary clues to help explain the mechanisms underlying the distinct clinical patterns that characterize NX and NXG.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4279948&req=5

fig05: Proposed molecular and cellular mechanisms for the appearance of skin lesions in patients with NX and NXG. Low levels of anti-inflammatory HDL-C (apoA-I) were associated with increased expression of chemokine receptor CCR2 in circulating monocytes and elevated levels of chemokines (MCP-1, IL-8, MIP-1α) and adhesion molecules (VCAM-1, ICAM-1), which might favour monocyte recruitment and homing to skin in patients with NX and NXG. This effect might be exacerbated in the case of NXG due to the presence of a high proportion of intermediate CD14++CD16+ monocytes. Moreover, increased levels of soluble receptors (sIL-6R, sTNFRI and TNFRII), which were also inversely correlated with plasma HDL-C (apoA-I) levels, contributed to the ‘xanthoma inflammatory profile’ observed in patients with NX and NXG. Although serum from both NX and NXG promoted cholesterol accumulation in macrophages, the appearance of foam cells in NXG likely also resulted from the impaired capacity of HDL particles (HDL3c) to promote macrophage cholesterol efflux. In addition, the presence of immune complexes (IgG anti-lipoproteins) that might enter into macrophage through phagocytosis via scavenger or Fcγ receptors may also contribute to foam-cell formations in both NXG and NX. Finally, the differential levels of EGF, IL-15 and IFNγ observed in NX and NXG subjects could provide some preliminary clues to help explain the mechanisms underlying the distinct clinical patterns that characterize NX and NXG.
Mentions: In conclusion, our present findings are integrated schematically in Fig.5. Herein, we report that NXG is characterized by an abnormal HDL phenotype associated with a unique inflammatory pattern, the preponderance of a specific monocyte subset and an impaired macrophage cholesterol homeostasis, probably due to interactions between MIg and lipoproteins. Although NXG is a relatively rare condition, our results contribute to the understanding of the cellular mechanisms involved in lipid accumulation.

Bottom Line: This accumulation was due in part to a significant reduction in the HDL capacity to promote cholesterol efflux from macrophages, which was not found in the case of NX.However, patients with NXG were distinguished by elevated levels of IL-15 and a marked increase in the rate of intermediate CD14++CD16+ monocytes.This study revealed that NXG is characterized by impaired macrophage lipid homeostasis associated with a systemic inflammatory profile that may result from the interaction of MIg and lipoproteins.

View Article: PubMed Central - PubMed

Affiliation: Département d'immunologie Clinique, Hôpital Saint Louis, Paris, France; EA3963, Université Paris 7 Denis Diderot, INSERM, IFR105, Institut Universitaire d'Hématologie, Paris, France.

Show MeSH
Related in: MedlinePlus