待解决的科学问题：
1. CD47/Sirpa KO为什么不会影响小鼠生长发育？（如果巨噬细胞主要借助CD47/Sirpa来区分非我）
因为除了CD47/Sirpa通路外，还需要一个促进吞噬的cytokine和细胞环境才会吞噬自体细胞。
2. what is the mechanism that initiates macrophages to phagocytose healthy self-cells?
但是健康自体细胞是否有受体，受体是哪个，目前还不知道。
Results
1. Acute Anemia in Mice Deficient of Cd47-Sirpα–Mediated Inhibition Under Inflammatory Conditions.
炎症模型：DSS(colitis), zymosan-induced peritonitis, LPS, and Freund’s complete adjuvant (CFA)-induced inflammation
Sirpa KO 在炎症小鼠中会出现贫血现象，即healthy self-cells会被部分吞噬。在健康小鼠中未发现明显生理缺馅。
且发现与IL17的分泌有关，IL17具有促进吞噬的作用：通过block—anti–IL-17 neutralization antibody, 过表达—colitis serum samples that contained high levels of IL-17，recombinant IL-17A正向、反向验证。
2. In Vivo Assessment of Macrophage Phagocytosis by Adoptive Transfer.
在健康状态下，Sirpa KO和CD47 KO小鼠都不能有效phagocytosis。
但是Sirpa KO和CD47 KO小鼠表现略有不同：Sirpa KO导致吞噬抑制被解除，则CD47+/- RBC都能够被部分吞噬（WT不吞噬CD47+ RBC）；而CD47 KO小鼠能够部分吞噬CD47- RBC，但无法识别自身RBC，即无法吞噬CD47+ RBC。
以上想法错误：因为Sirpa KO即意味着无法识别CD47则更加无法吞噬。
在炎症状态下，能够大大激发Sirpa KO和CD47 KO小鼠的吞噬表现：
1）DSS下，Sirpa KO小鼠能够有效吞噬自身细胞即CD47+ RBC，即自体细胞识别被破坏？
2）在更强的炎症因子刺激下，IL17A，CD47 KO小鼠虽然仍无法吞噬自身RBC，但是也能够吞噬CD47-RBC
3. Ex Vivo Studies of Macrophage Phagocytosis.
使用3种Mac：splenic macrophages, peritoneal macrophages (PEMs), and bone marrow-derived macrophages (BMDMs)
only red pulp macrophages freshly isolated from WT mice were phagocytic toward self-cells, whereas other splenic macrophages, PEMs and BMDMs, and red pulp macrophages from mutant mice were all incapable of phagocytosis irrespective of the Cd47 expression on target cells.
all macrophages, irrespective of their origins and phagocytic behavior toward self-cells, were potent phagocytes toward Escherichia coli, zymosan, apoptotic cells, antibody, or complement-bound targets.
说明：巨噬细胞异质性强，吞噬能力及介导吞噬的机制不同
4. Macrophage Phagocytic Plasticity.
炎症因子刺激：LPS, IL-17A, IL-6, TNFa, IL-1b, IFNγ, IL-10
注：Thioglycollate, a reagent commonly used to elicit macrophages in the peritoneum.
注意在supplementary里面额外放了hCD47的target cell（与murine Sirpa不符合）
completely lost this capacity after 2 d of culturing, but maintained phagocytosis toward E. coli, zymosan, apoptotic cells, and antibody- or complement-bound targets.
LPS and IL-17A, which dramatically rekindled the “culture-retarded” WT spleen macrophages for potent phagocytosis toward Cd47− RBCs.
5. Signaling Mechanisms Regulating Macrophage Phagocytosis Toward Self.
通过相关常见信号通路MAP, Src, Jak, NF-kB的抑制剂来研究stimuli激活吞噬自体细胞的背后机制。
cytokine增强自体细胞吞噬可能与Syk信号通路有关。
除此之外，作者发现了一个更强的吞噬激活分子——PMA, the PKC activator
进一步研究PMA是否通过Syk通路起作用：
6. What Is the Phagocytic Receptor on Macrophages for Uptaking Healthy Self-Cells?
作者未发现影响自体细胞吞噬的关键巨噬细胞表面受体，但是排除了calreticulin(CRT)-LRP1, scavenger receptor A (anti–SR-A)or Fc receptors (anti-Cd16/Cd32), or inhibitors against scavenger receptor B (BLT1), dectin (laminarin), and complement (heparin)的影响。
To date, the molecules serving as the phagocytic ligands on healthy self-cells, together with the phagocytic receptor on macrophages, remain undefined.
7. Different Spleen Environments in WT Mice and Mutant Mice.
通过adoptive transfer nonphagocytic Sirpα− BMDMs into WT mice实验发现Sirpa KO的巨噬细胞可以重新获得吞噬自体细胞的能力。
说明在一定的组织微环境（cytokine stimuli）下，CD47-Sirpa才会发挥抑制作用。
注意，WT小鼠在没有stimuli强刺激下仍然能重新激活KO Mac！事实上SPF和germ-free环境下的小鼠吞噬能力会下降。
分析WT和KO mice脾环境：cytokine分泌水平（Sirpα−/− and Cd47−/− mice produce relatively higher levels of IL-10, but lesser IL-17 and IL-6 compared with those from WT mice）和 免疫辅助细胞的差异（deficit of Cd11c+ dendritic cells (DCs), especially the major mi�gratory and antigen-presenting Cd8− DCs and Cd4+ Th lymphocyte）
RNAseq
